Publications
2026
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Can metformin prolong pregnancy in preterm pre-eclampsia? Study protocol for a Nordic multicentre randomised placebo-controlled trial (PI4)
INTRODUCTION: Pre-eclampsia affects 2–8% of all pregnancies and remains a leading cause of maternal and perinatal morbidity and mortality. A randomised trial in South Africa suggested metformin used to treat preterm pre-eclampsia (26–32 weeks’ gestation) may prolong pregnancy by 7 days compared with standard care. However, this finding was borderline significant and requires validation in higher-resource settings and in diverse populations. Here, we present a Nordic multicentre trial protocol... -
Population-scale immune multiome atlas reveals regulatory disease mechanisms
Most disease-associated genetic variants lie in non-coding regions^(1,2), yet mechanistic insights are limited by the lack of an empirical framework for characterizing the molecular consequences of regulatory variation. Single-cell molecular quantitative trait locus (QTL) mapping^(3,4) connects variants to gene regulation but lacks the power and simultaneous measurements to trace mechanisms from chromatin to expression⁵. Here we show that population-scale simultaneous profiling of chromatin... -
Cohort profile update: the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC)
PURPOSE: The Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) study was originally established between 2008 and 2011 to develop a nationwide clinical and genomic database. By enrolling women with and without pre-eclampsia (PE), alongside their partners and infants, the study aims to identify the genetic and molecular determinants of PE. This update summarises the final dataset, reviews key findings since the 2016 cohort profile, and outlines current research directions. -
XXYLT1 and Mendelian Retinal Dystrophy
CONCLUSIONS AND RELEVANCE: This GWAS identified an association between XXYLT1 and IRD. These results affirm that GWAS in a founder population can be used as a potential tool for the discovery of rare mendelian disease genes and that XXYLT1 should be considered in clinical IRD gene panels. -
Maternal and fetal treatment outcomes of pregnancy-related aneurysmal subarachnoid hemorrhage: a nationwide study
CONCLUSIONS: Aneurysmal SAH during pregnancy is associated with exceptionally low maternal and neonatal mortality. All maternal and fetal fatalities were due to sudden prehospital deaths. Pregnancy-related immunological modulation and its potential benefits on aSAH outcomes represent a compelling topic for future research. -
Cohort Profile Update: The Finnish Gestational Diabetes (FinnGeDi) study
No abstract -
Performance of the Pre-Eclampsia Integrated Estimate of Risk-Machine Learning (PIERS-ML) model in a Kenyan cohort of women with pre-eclampsia- a retrospective test derivation validation study
CONCLUSION: In a high-morbidity Kenyan cohort, the PIERS-ML tool accurately identified personalised risk in women admitted with pre-eclampsia. -
Long-term alterations in serum metabolite profiles in women with a history of preeclampsia -FINNCARE study
Preeclampsia (PE) is a multifaceted pregnancy condition which increases the risk of cardiometabolic diseases later in life. Long-term follow-up data on metabolome utilizing novel metabolomic techniques are needed to gain insights into metabolism after PE and non-PE pregnancies for identifying potential areas of investigation that could assist in predicting and managing future health risks. The objective of the current study was to characterize long-term metabolome in women with and without a... -
Polygenic Risk Impacts Lifetime Risk and Prognosis of Glaucoma
CONCLUSIONS: In this large biobank study, a glaucoma PRS effectively stratified individuals according to their lifetime risk of glaucoma, with substantial stratification evident already by midlife. The PRS provided a more precise risk assessment than family history alone, and it was effective in stratifying individuals based on several prognostic measures, including medical treatment escalation and surgical interventions. These findings support the potential usefulness of PRS-guided screening... -
Association and risk prediction of 19 complex diseases with polygenic scores and socioeconomic status
CONCLUSIONS: Genetic variation and social circumstances are linked to differences in disease risk both independently, and in combination with one another. Considering both factors modestly improves identification of higher-risk groups and highlights the value of accounting for social context alongside inherited variation in population-level assessments. -
Scalable biological-cognitive profiling for Alzheimer's disease in the population
Plasma phosphorylated tau217 has been suggested as a core biomarker for establishing a biological Alzheimer's disease diagnosis. This blood biomarker has not been studied together with scalable cognitive assessment tools in population-based samples. We investigated the prevalence of cognitive and Alzheimer's disease biomarker abnormalities and associations between plasma phosphorylated tau217 and remotely measured cognitive function in individuals without dementia. We used a population-based... -
Multi-ancestry, trans-generational GWAS meta-analysis of gestational diabetes and glycaemic traits during pregnancy reveals limited evidence of pregnancy-specific genetic effects
Gestational diabetes mellitus (GDM) affects ~14% of pregnancies and increases maternal type 2 diabetes mellitus (T2DM) risk. The GenDiP Consortium presents trans-generational, multi-ancestry genome-wide association study meta-analyses of GDM and pregnancy glycemic traits in up to 38,305 GDM cases and 776,145 controls. We identify 37 GDM-associated loci (7 novel) and five novel loci for pregnancy glycemic traits, all operating through the maternal genome. We classify 12 GDM variants with stronger... -
Genome-wide meta-analysis identifies genetic drivers of bile acid metabolism in intrahepatic cholestasis of pregnancy
Intrahepatic cholestasis of pregnancy, which affects 0.2-2% of pregnancies, is characterized by pruritus, increased aminotransferase activity and elevated serum bile acids. Previous studies have implicated liver-enriched genes in intrahepatic cholestasis of pregnancy. We conducted a meta-analysis of intrahepatic cholestasis of pregnancy genome-wide association studies in the FinnGen study, deCODE, Estonian Biobank, the Danish Blood Donor Study and Copenhagen Hospital Biobank with 4,738 women... -
Analgesic nonresponsiveness to nitrous oxide during labour as a risk factor for postpartum depression: a prospective observational cohort study
No abstract -
Evaluation of Genetics in the Association Between Cardiorespiratory Fitness and Health: Insights from a Genome-Wide Polygenic Score for Cardiorespiratory Fitness in the FinnGen and HUNT cohorts
We evaluated how much cardiorespiratory fitness (CRF)-related genetics contribute to the risk of common noncommunicable diseases (NCDs) and mortality, and whether individuals with different levels of CRF and genetic predispositions differ in health characteristics. We used a validated SBayesR-based genome-wide polygenic score, leveraging information from 905 707 single-nucleotide polymorphisms, to measure CRF genetics (PGS CRF). Associations with register-based incident NCDs and mortality were... -
A Population-Based Study of Posterior Reversible Encephalopathy Syndrome and Reversible Cerebral Vasoconstriction Syndrome During Pregnancy and Puerperium
CONCLUSIONS: Pregnancy-associated PRES and RCVS are potentially life-threatening, rare conditions that can result in hemorrhagic stroke. PRES ± RCVS is strongly associated with preeclampsia with severe features, whereas puerperal RCVS seems to be a separate, later-occurring condition. -
Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and... -
Gestational diabetes and spousal health: the Finnish gestational diabetes study
The spouses of women with gestational diabetes mellitus (GDM) seem to be at risk of developing type 2 diabetes and cardiovascular diseases (CVDs). We comparatively analysed the risk factors, lifestyle, socioeconomic factors, and health of the spouses of women with (cases, n = 599) and without (controls, n = 586) GDM. This cross-sectional study utilized data from the Finnish Gestational Diabetes study. Data of the spouses were collected using a structured questionnaire: socioeconomic factors,... -
Genetic architecture of lumbar spinal stenosis
Lumbar spinal stenosis (LSS) affects over 100 million people globally, with an increasing incidence due to an ageing population. While LSS is known to be heritable, its genetic basis remains poorly understood. We conduct a genome-wide meta-analysis of LSS in 40,303 cases and 741,469 controls. We identify 73 previously unreported loci in addition to 15 known loci, and highlight spinal degeneration as a key pathogenic mechanism. In 12,784 surgically treated cases, we discover five loci... -
Quantifying risk modifiers of hereditary hemochromatosis using genomic and electronic health record data
CONCLUSIONS: We demonstrated that use of large-scale electronic health record data allows for precise quantification of individual-level risk, which we present as risk tables to support clinical practice. Furthermore, our findings suggest that hemochromatosis may be under-recognized in Finland. -
Associations between maternal prepregnancy body mass index and maternal and cord blood metabolome
CONCLUSION: Maternal pBMI is associated with alterations in fetal cord blood metabolome. Maternal and fetal metabolomes are associated, and associations vary according to maternal pBMI. -
Long-Term Recovery, Morbidity, and Mortality After Maternal Ischemic Stroke
BACKGROUND AND OBJECTIVES: The long-term prognosis after maternal ischemic stroke (IS) remains understudied. The objectives were to examine if mortality and long-term morbidity are more frequent in women with prior maternal IS compared with women without a pregnancy-related stroke and to assess recovery in maternal IS patients based on functional outcomes and vocational status. -
Impact of Preeclampsia Duration on Long-Term Cardiovascular Disease Risk
CONCLUSIONS: Long-term CVD risk before age 55 is estimated to increase 1% to 2% per day from preeclampsia diagnosis to delivery. Women with preeclampsia might benefit from early delivery. -
Gestational diabetes mellitus and offspring health: A 12-year register-based analysis of specialized health care utilization in Finland
CONCLUSIONS: Children exposed to maternal GDM required more specialized health care services than unexposed children, with increased utilization of specialized health care observed across all age categories up to 12 years of age. -
Stroke Recurrence and Pregnancy Outcomes in the Subsequent Pregnancies After Maternal Ischemic Stroke
CONCLUSIONS: Although most pregnancies proceed without complications, the subsequent pregnancies of women with a prior maternal IS are high-risk pregnancies that require careful planning and surveillance. They are frequently complicated with diabetes and hypertensive disorders of pregnancy, and the recurrence of IS or transient ischemic attack is notable.
2025
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XXYLT1 and Mendelian Retinal Dystrophy
CONCLUSIONS AND RELEVANCE: This GWAS identified an association between XXYLT1 and IRD. These results affirm that GWAS in a founder population can be used as a potential tool for the discovery of rare mendelian disease genes and that XXYLT1 should be considered in clinical IRD gene panels. -
Genetic liability to psoriasis predicts severe disease outcomes
CONCLUSIONS: The psoriasis susceptibility PRS demonstrates utility and may be more effective than established epidemiological factors, as a stratification tool to identify those individuals that are at greatest risk of severe disease and may benefit most from early intervention. -
Impact of Preeclampsia Duration on Long-Term Cardiovascular Disease Risk
CONCLUSIONS: Long-term CVD risk before age 55 is estimated to increase 1% to 2% per day from preeclampsia diagnosis to delivery. Women with preeclampsia might benefit from early delivery. -
Gestational diabetes mellitus and offspring health: A 12-year register-based analysis of specialized health care utilization in Finland
CONCLUSIONS: Children exposed to maternal GDM required more specialized health care services than unexposed children, with increased utilization of specialized health care observed across all age categories up to 12 years of age. -
Stroke Recurrence and Pregnancy Outcomes in the Subsequent Pregnancies After Maternal Ischemic Stroke
CONCLUSIONS: Although most pregnancies proceed without complications, the subsequent pregnancies of women with a prior maternal IS are high-risk pregnancies that require careful planning and surveillance. They are frequently complicated with diabetes and hypertensive disorders of pregnancy, and the recurrence of IS or transient ischemic attack is notable. -
The Effect of Metformin on Insulin Requirement, Glycaemic Control and Weight Gain in Type 1 Diabetes During Pregnancy-a Randomised, Placebo-Controlled Multicentre Study
CONCLUSIONS: Metformin was not shown to affect total insulin change but reduced the prandial insulin change and improved weight gain control especially in insulin-resistant subgroups. These findings warrant further studies on metformin as an adjunctive medicine. -
Lifestyle-based and psychological interventions during pregnancy and risk of obesity and obesity-associated metabolic complications in the offspring: A scoping review
CONCLUSIONS: A limited number of studies have evaluated offspring outcomes beyond the neonatal period. Lifestyle-based interventions including psychological components are particularly scarce. The research conducted demonstrated only a minor impact on childhood anthropometric and metabolic outcomes; however, the interpretation of these findings is hampered by a considerable risk of bias, largely due to missing offspring data. -
Large-scale genome-wide analyses with proteomics integration reveal novel loci and biological insights into frailty
Frailty is a clinically relevant phenotype with notable gaps in our understanding of its etiology. Using the Hospital Frailty Risk Score (HFRS) to define frailty, we performed a genome-wide association study in FinnGen (N = 500,737), replicated the results in the UK Biobank (N = 407,463) and performed a meta-analysis. We prioritized genes through colocalization with expression, splicing and protein quantitative trait loci and proteomics integration. We identified 53 independent lead variants... -
Early abduction treatment versus observation in Barlow-positive and mildly unstable hips
CONCLUSION: Observation for about a month in clinically mildly unstable hips with or without Barlow positive signs seems safe regarding the recovery of alpha angles, treatment duration and treatment failures. More research is needed for longer observation times. -
Long-term cardiovascular risk in women with hypertensive disorders of pregnancy: Insights from polygenic risk scores
CONCLUSIONS: In women with PE or any HDP, a high genetic risk for PE, high SBP, CAD, and stroke further increases the overall risk of CVD. Among women with normotensive pregnancies, a high genetic risk confers only a modest increase in CVD risk. In evaluating long-term CVD risk, clinical risk assessment, including obstetric history, appears to outperform genetic risk evaluation using PRSs. -
Genetic Loci Associated With Periodontitis: The FinnGen Study Based on National Health Registers
CONCLUSIONS: Our GWAS suggests that genetic variation contributing to immune dysregulation is involved in the pathogenesis of periodontitis, which has considerable genetic similarity with other complex traits. -
Genetic association of preeclampsia to von Willebrand factor and its size-regulator ADAMTS13
Preeclampsia is a common pregnancy-specific vascular disorder that develops during the second half of pregnancy. Preeclampsia shares features with thrombotic microangiopathies. Here we analyzed whether sequence variants in the coagulation system genes predispose to preeclampsia. We performed targeted exomic sequencing of 58 genes in a total of 615 preeclamptic women and 2094 controls. A common missense variant rs1800385 (Val1565Leu) in the gene coding for von Willebrand Factor (VWF) (OR=1.72,... -
Exploring the association between gestational diabetes exposure and mental and behavioural disorders in offspring: the Finnish gestational diabetes (FinnGeDi) register-based study
CONCLUSIONS: Children exposed to maternal GDM have a higher prevalence of mental and behavioural disorders compared with non-exposed children. Notably, GDM exposure was shown to be an independent risk factor for these disorders in boys only. -
Cardiometabolic health 8-12 years after pre-eclampsia: Role of obesity and gestational diabetes (FINNCARE study)
CONCLUSIONS: Women with PE + GDM and with superimposed PE exhibited an adverse cardiometabolic profile characterized by high BMI. This highlights the need for targeted cardiovascular prevention. Women with de novo PE should undergo regular blood pressure monitoring. -
The recurrence risk of gestational diabetes according to the number of abnormal values in the oral glucose tolerance test
CONCLUSIONS: Primiparous women with one abnormal glucose value in the first OGTT have remarkable odds of GDM recurrence, with the odds doubling when there are two or three abnormal values during the first pregnancy. These findings can be used when planning effective counseling, prevention, and screening strategies for GDM in the subsequent pregnancy. -
Role of oxysterol 4β-hydroxycholesterol and liver X receptor alleles in pre-eclampsia
CONCLUSIONS: Our results demonstrate that plasma 4βHC and genetic LXR variants do not play a major role in PE and BP regulation during pregnancy. However, key LXR target genes involved in lipid metabolism were expressed differently in normal and PE pregnancies. Further research is needed to understand the complexities of oxysterols, LXRs, and their potential contributions to placental function and pregnancy outcomes. -
Monoallelic TYROBP deletion is a novel risk factor for Alzheimer's disease
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population... -
External causes are leading causes of death in women of reproductive age: a registry study on maternal perinatal health, hypertensive pregnancy disorders and mortality in Finland
CONCLUSIONS: Reproductive history, specifically preventable and CVD cause, has a significant role in mortality of women of reproductive age. Women have an increased risk of CVD death, and reduced survival of CVD mortality, if they have PE or other HDP, in the pregnancy associated with their first birth. -
Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum
Genome-wide association studies (GWASs) may help inform the etiology of infertility. Here, we perform GWAS meta-analyses across seven cohorts in up to 42,629 cases and 740,619 controls and identify 25 genetic risk loci for male and female infertility. We additionally identify up to 269 genetic loci associated with follicle-stimulating hormone, luteinizing hormone, estradiol and testosterone through sex-specific GWAS meta-analyses (n = 6,095-246,862). Exome sequencing analyses reveal that women... -
Narcolepsy as a potential risk factor for Schizophrenia
Narcolepsy is a severe sleep disorder with characteristics of fatigue, fragmented sleep, cataplexy and hypnagogic hallucinations. Earlier clinical studies have reported the onset of schizophrenia after narcolepsy but the causality behind narcolepsy and schizophrenia is unknown. Our goal was to understand the causality between narcolepsy and schizophrenia. To estimate the comorbidity between narcolepsy and schizophrenia, we employed data from the FinRegistry that contains data for the total... -
Determination of steroid reference intervals in a pregnancy population
Steroids, including mineralocorticoids, glucocorticoids, and sex hormones play a critical role in pregnancy. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis offers an opportunity to conduct simultaneous multiplex steroid analysis within a given sample. This paper describes the LC-MS/MS steroid analysis method developed for assessing plasma specific reference ranges of 18 steroids from plasma samples (200 µL) of pregnant women participating in the PREDO study. Samples were... -
Broadening the Phenotype Spectrum of MECP2 Variants in Men
CONCLUSIONS: The p.Ala140Val mutation of MECP2 in males is associated with a rare X-chromosomal developmental disorder with highly variable phenotypes. Further studies are needed to better understand all those influencing factors that can explain phenotypic differences within the same genotype to find optimal medicinal therapies. -
Metabolic profiles of meconium in preeclamptic and normotensive pregnancies
CONCLUSION: PE is associated with alterations in the meconium metabolome of infants. The differing abundances of several metabolites show alterations in the interaction between the fetoplacental unit and mother in PE, but whether they are a cause or an effect of the disorder remains to be further investigated. -
Genome-wide association study of anterior uveitis
CONCLUSION: We identified six anterior uveitis-associated loci, including three novel loci with genome-wide significance. Our findings deepen our understanding of the genetic basis of anterior uveitis and the genetic connections between anterior uveitis and immune-related disorders, providing a foundation for further research and potential therapeutic interventions. -
Understanding rare genetic variants within the terminal pathway of complement system in preeclampsia
Preeclampsia is a common multifactorial disease of pregnancy. Dysregulation of complement activation is among emerging candidates responsible for disease pathogenesis. In a targeted exomic sequencing study of 609 women with preeclampsia and 2092 non-preeclamptic controls, we identified 14 variants within nine genes coding for components of the membrane attack complex (MAC, C5b-9) that are associated with preeclampsia. We found two rare missense variants in the C5 gene that predispose to... -
Perinatal and neonatal outcomes in gestational diabetes: The importance of the number of abnormal values in an oral glucose tolerance test
CONCLUSIONS: The risk of adverse perinatal and neonatal outcomes is significantly higher in women with two or more abnormal OGTT values than in those with one abnormal value. -
Genetic Susceptibility to Acute Viral Bronchiolitis
CONCLUSIONS: Our results suggest that genetic variants in CDHR3 and GSDMB modulate susceptibility to bronchiolitis, especially when caused by viruses other than RSV. Severe bronchiolitis in infancy may trigger the development of asthma in genetically susceptible individuals, or it could be a marker of genetic predisposition to asthma. -
Maternal Antenatal Depression Is Associated With Metabolic Alterations That Predict Birth Outcomes and Child Neurodevelopment and Mental Health
CONCLUSIONS: AD was associated with alterations in 15 metabolic measures, which collectively improved the prediction of AD over its risk factors and birth, neurodevelopmental, and mental health outcomes in children over AD. These metabolic measures may become biomarkers that can be used to identify at-risk mothers and children for personalized interventions. -
Intracranial Arteriovenous Malformations During Pregnancy and Puerperium-A Retrospective Nationwide Population-Based Cohort Study
CONCLUSION: Most mothers in the study had prior pregnancies, suggesting a potentially weaker association between AVM rupture and pregnancy compared to previous reports. Notably, 2 AVM ruptures occurred during spontaneous vaginal deliveries. Outcomes were generally favorable in both mothers and infants. More research is needed to refine our understanding of the optimal timing for invasive treatment during pregnancy.
2024
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XXYLT1 and Mendelian Retinal Dystrophy
CONCLUSIONS AND RELEVANCE: This GWAS identified an association between XXYLT1 and IRD. These results affirm that GWAS in a founder population can be used as a potential tool for the discovery of rare mendelian disease genes and that XXYLT1 should be considered in clinical IRD gene panels. -
Performance of the Pre-Eclampsia Integrated Estimate of Risk-Machine Learning (PIERS-ML) model in a Kenyan cohort of women with pre-eclampsia- a retrospective test derivation validation study
CONCLUSION: In a high-morbidity Kenyan cohort, the PIERS-ML tool accurately identified personalised risk in women admitted with pre-eclampsia. -
Monoallelic TYROBP deletion is a novel risk factor for Alzheimer's disease
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population... -
Understanding rare genetic variants within the terminal pathway of complement system in preeclampsia
Preeclampsia is a common multifactorial disease of pregnancy. Dysregulation of complement activation is among emerging candidates responsible for disease pathogenesis. In a targeted exomic sequencing study of 609 women with preeclampsia and 2092 non-preeclamptic controls, we identified 14 variants within nine genes coding for components of the membrane attack complex (MAC, C5b-9) that are associated with preeclampsia. We found two rare missense variants in the C5 gene that predispose to... -
Novel loci and biomedical consequences of iron homoeostasis variation
Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait expression,... -
Inherited infertility: Mapping loci associated with impaired female reproduction
Female infertility is a common and complex health problem affecting millions of women worldwide. While multiple factors can contribute to this condition, the underlying cause remains elusive in up to 15%-30% of affected individuals. In our large genome-wide association study (GWAS) of 22,849 women with infertility and 198,989 control individuals from the Finnish population cohort FinnGen, we unveil a landscape of genetic factors associated with the disorder. Our recessive analysis identified a... -
Genome-wide meta-analysis conducted in three large biobanks expands the genetic landscape of lumbar disc herniations
Given that lumbar disc herniation (LDH) is a prevalent spinal condition that causes significant individual suffering and societal costs, the genetic basis of LDH has received relatively little research. Our aim is to increase understanding of the genetic factors influencing LDH. We perform a genome-wide association analysis (GWAS) of LDH in the FinnGen project and in Estonian and UK biobanks, followed by a genome-wide meta-analysis to combine the results. In the meta-analysis, we identify 41... -
Perinatal and neonatal outcomes in gestational diabetes: The importance of the number of abnormal values in an oral glucose tolerance test
CONCLUSIONS: The risk of adverse perinatal and neonatal outcomes is significantly higher in women with two or more abnormal OGTT values than in those with one abnormal value. -
Maternal psychological distress and temperament traits in children from infancy to late childhood
CONCLUSIONS: Maternal psychological distress during pregnancy is associated with individual differences and change in child temperament from infancy to late childhood. However, distress during pregnancy has a smaller effect on late childhood temperament than maternal concurrent distress. -
Development and validation of a prognostic model to predict birth weight: individual participant data meta-analysis
CONCLUSIONS: The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other... -
Limiting access to assisted reproductive technologies for males of advanced age-Pros and cons from a Nordic perspective
It is not controversial to state that parental age is increasing in several countries. But how to deal with this increase might be. Some Nordic countries have set an upper age limit for females seeking assisted reproduction in their national legislation, but none have done so for males. There are also recommendations in place that restrict access to publicly funded assisted reproduction for both females and males of advanced age in some Nordic countries. As recent data now show somatic and... -
Risk Variants Associated With Normal Pressure Hydrocephalus: Genome-Wide Association Study in the FinnGen Cohort
BACKGROUND AND OBJECTIVES: Large-scale genome-wide studies of chronic hydrocephalus have been lacking. We conducted a genome-wide association study (GWAS) in normal pressure hydrocephalus (NPH). -
Maternal Antenatal Depression Is Associated With Metabolic Alterations That Predict Birth Outcomes and Child Neurodevelopment and Mental Health
CONCLUSIONS: AD was associated with alterations in 15 metabolic measures, which collectively improved the prediction of AD over its risk factors and birth, neurodevelopmental, and mental health outcomes in children over AD. These metabolic measures may become biomarkers that can be used to identify at-risk mothers and children for personalized interventions. -
Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage
Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severe impact on maternal-fetal health. We identified five genetic loci linked to PPH in a meta-analysis. Functional annotation analysis indicated candidate genes HAND2, TBX3 and RAP2C/FRMD7 at three loci and showed that at each locus, associated variants were located within binding... -
Cardiac Structure and Function in 8- to 12-Year-Old Children Following In-Utero Exposure to Preeclampsia (FINNCARE Study)
CONCLUSIONS: Preadolescent PE children display a more globular-shaped right ventricle with higher longitudinal systolic displacement as well as mildly altered diastolic indices, with the alterations being pronounced in early-onset preeclampsia. Lean body mass and adiposity are independently related with LVM and left atrial volume, and systolic blood pressure with LVM in both PE and non-PE children. These unfavorable associations indicate remodeling of cardiac structure in young children also... -
Intracranial Arteriovenous Malformations During Pregnancy and Puerperium-A Retrospective Nationwide Population-Based Cohort Study
CONCLUSION: Most mothers in the study had prior pregnancies, suggesting a potentially weaker association between AVM rupture and pregnancy compared to previous reports. Notably, 2 AVM ruptures occurred during spontaneous vaginal deliveries. Outcomes were generally favorable in both mothers and infants. More research is needed to refine our understanding of the optimal timing for invasive treatment during pregnancy. -
Fetal cord plasma herpesviruses and preeclampsia: an observational cohort study
A previous study suggested that fetal inheritance of chromosomally integrated human herpesvirus 6 (ici-HHV6) is associated with the hypertensive pregnancy disorder preeclampsia (PE). We aimed to study this question utilizing cord plasma samples (n = 1276) of the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort: 539 from a pregnancy with PE and 737 without. We studied these samples and 30 placentas from PE pregnancies by a multiplex qPCR for the DNAs of all nine human herpesviruses.... -
Long-Term Mortality, Recovery, and Vocational Status After a Maternal Stroke: Register-Based Observational Case-Control Study
BACKGROUND AND OBJECTIVES: Maternal stroke is a rare event with an increasing incidence. Data on the long-term prognosis after a maternal stroke are limited. We aimed to examine long-term mortality, recovery, vocational status and morbidity after a maternal stroke in a population-based setting including a comparison with matched, stroke-free controls. -
TWINGEN: protocol for an observational clinical biobank recall and biomarker cohort study to identify Finnish individuals with high risk of Alzheimer's disease
INTRODUCTION: A better understanding of the earliest stages of Alzheimer's disease (AD) could expedite the development or administration of treatments. Large population biobanks hold the promise to identify individuals at an elevated risk of AD and related dementias based on health registry information. Here, we establish the protocol for an observational clinical recall and biomarker study called TWINGEN with the aim to identify individuals at high risk of AD by assessing cognition, health and... -
Serum hydroxysteroid (17beta) dehydrogenase 1 concentration in pregnant women correlates with pregnancy-associated plasma protein A but does not serve as an independent marker for preeclampsia†
Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) is a steroid synthetic enzyme expressed in ovarian granulosa cells and placental syncytiotrophoblasts. Here, HSD17B1 serum concentration was measured with a validated immunoassay during pregnancy at three time points (12-14, 18-20 and 26-28 weeks of gestation). The concentration increased 2.5-fold (P < 0.0001) and 1.7-fold (P = 0.0019) during the follow-up period for control women and women who later developed preeclampsia (PE), respectively, and... -
Risk assessment of hypertensive disorders of pregnancy and other adverse pregnancy outcomes after frozen embryo transfers following an artificial cycle: A retrospective cohort study
CONCLUSION: The risk of HDP and several other maternal complications seems to be increased after AC-FET compared with CL-FET. Our findings support most earlier studies regarding HDP and add to the knowledge on other maternal and perinatal risks involved in AC-FET, including an increased risk of milder forms of placental retention. More studies are needed to confirm these findings. -
Delayed versus early delivery leads to similar outcome in selected cases of preeclampsia in the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort
CONCLUSION: Early and delayed delivery lead to comparable outcomes in this cohort. Expectant management could be beneficial in women with an unripe cervix or preterm preeclampsia without severe features. -
Rare variants in genes coding for components of the terminal pathway of the complement system in preeclampsia
Preeclampsia is a common multifactorial disease of pregnancy. Dysregulation of the complement activation is among emerging candidates responsible for disease pathogenesis. In a targeted exomic sequencing study we identified 14 variants within nine genes coding for components of the membrane attack complex (MAC, C5b-9) that are associated with preeclampsia. We found two rare missense variants in the C5 gene that predispose to preeclampsia (rs200674959: I1296V, OR (CI95) = 24.13 (1.25-467.43),... -
Clinical features of preeclampsia and hypertensive disorders in pregnancies after different frozen embryo transfer regimens
CONCLUSIONS: Among FET patients with PE, the risk of PPH wasincreased in pregnancies after cycles without a CL, compared to cycles with a CL. The presence or absence of a CL did noteffectthe severity of PE and GH, the duration of pregnancy or blood pressure levels. -
Genetic risk of type 2 diabetes modifies the association between lifestyle and glycemic health at 5 years postpartum among high-risk women
CONCLUSIONS: These results extend our previous findings from pregnancy and first postpartum year demonstrating that still at 5 years postpartum, healthy lifestyle is associated with a lower risk of prediabetes/diabetes only among women at the highest genetic risk of type 2 diabetes. -
Neonatal outcomes according to different glucose threshold values in gestational diabetes: a register-based study
BACKGROUND: Mild hyperglycaemia is associated with increased birth weight but association with other neonatal outcomes is controversial. We aimed to study neonatal outcomes in untreated mild hyperglycaemia using different oral glucose tolerance test (OGTT) thresholds. -
Acute recanalization therapy for ischemic stroke during pregnancy and puerperium
CONCLUSIONS: In this small nationwide cohort of maternal ISs, the complications of recanalization therapy were rare, and the outcomes were similar in IVT-treated maternal IS patients and controls. Maternal ISs should not be excluded from recanalization therapy in otherwise eligible situations. -
Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum
Genome-wide association studies (GWASs) may help inform treatments for infertility, whose causes remain unknown in many cases. Here we present GWAS meta-analyses across six cohorts for male and female infertility in up to 41,200 cases and 687,005 controls. We identified 21 genetic risk loci for infertility (P≤5E-08), of which 12 have not been reported for any reproductive condition. We found positive genetic correlations between endometriosis and all-cause female infertility (r (g)=0.585,... -
Machine learning-enabled maternal risk assessment for women with pre-eclampsia (the PIERS-ML model): a modelling study
BACKGROUND: Affecting 2-4% of pregnancies, pre-eclampsia is a leading cause of maternal death and morbidity worldwide. Using routinely available data, we aimed to develop and validate a novel machine learning-based and clinical setting-responsive time-of-disease model to rule out and rule in adverse maternal outcomes in women presenting with pre-eclampsia. -
Patterns of reproductive health in inflammatory rheumatic diseases and other immune-mediated diseases: a nationwide registry study
CONCLUSION: Rheumatic diseases have a broad impact on reproductive health, with effects comparable with that of several other IMDs. Of the rheumatic diseases, SLE and SS conferred the largest risk increases on perinatal adverse event outcomes. -
Maternal gestational hypertension, smoking and pre-eclampsia are associated with metabolic dysfunction-associated fatty liver disease in overweight offspring
CONCLUSIONS: Maternal smoking, gestational hypertension and pre-eclampsia were associated with MAFLD among overweight or obese children. Further prospective studies are needed to verify causal relationships. -
Comprehensive Inherited Risk Estimation for Risk-Based Breast Cancer Screening in Women
CONCLUSION: Using real-life screening data, this study demonstrates the effectiveness of a breast cancer PRS for risk stratification, alone and combined with FH and PVs. Further research is required to evaluate their impact in a prospective risk-stratified screening program, including cost-effectiveness. -
Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry
CONCLUSIONS: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically... -
Associations of polymetabolic risk of high maternal pre-pregnancy body mass index with pregnancy complications, birth outcomes, and early childhood neurodevelopment: findings from two pregnancy cohorts
CONCLUSIONS: Maternal BMI-defined metabolome improves the prediction of pregnancy complications, birth outcomes, and neurodevelopment in children over anthropometric BMI. The novel, BMI-related PMRSs generated based on the BMI-defined metabolome have the potential to become biomarkers identifying at-risk mothers and their children for timely targeted interventions even at the level of maternal non-obesity and normal weight. -
High-Resolution Genotyping of Formalin-Fixed Tissue Accurately Estimates Polygenic Risk Scores in Human Diseases
Formalin-fixed paraffin-embedded (FFPE) tissues stored in biobanks and pathology archives are a vast but underutilized source for molecular studies on different diseases. Beyond being the "gold standard" for preservation of diagnostic human tissues, FFPE samples retain similar genetic information as matching blood samples, which could make FFPE samples an ideal resource for genomic analysis. However, research on this resource has been hindered by the perception that DNA extracted from FFPE... -
Sex-specific genetic risks for adverse outcomes after coronary revascularization procedures
Men and women have differing risks of adverse events after revascularization procedures and these differences could be partially driven by genetics. We studied the sex-specific differences in associations of polygenic risk scores (PRSs) with atrial fibrillation (AF), ischaemic stroke (STR), intracranial haemorrhage (ICH), myocardial infarction (MI) and gastrointestinal haemorrhage (GIH) in coronary revascularization patients. The study cohort comprised 5561 and 17 578 revascularized women and... -
Validation of the Finnish Care register for Health Care diagnoses for preeclampsia, gestational diabetes and preterm delivery
CONCLUSIONS: FCR registry diagnoses for PE have satisfactory sensitivity and high specificity. Diagnoses for GDM and preterm delivery have lower sensitivity limiting their use in studies, and data from MBR should be preferred when studying preterm deliveries. -
Endometrial preparation protocols prior to frozen embryo transfer - convenience or safety?
The number of frozen embryo transfer (FET) cycles is increasing rapidly worldwide. Different endometrial preparations for FET result in comparable live birth rates. However, several recent publications have reported higher maternal risks for hypertensive disorders of pregnancy (HDP), pre-eclampsia and postpartum haemorrhage (PPH) in programmed cycles (PC-FET) compared with natural cycles and modified natural cycles with an intact corpus luteum. Nevertheless, PC-FET is frequently used in... -
Preeclampsia-exposed children's heart rate variability 8-12 yr after index pregnancy: FINNCARE study
Preeclampsia is related with elevated systolic blood pressure (SBP) in children. We studied if preeclampsia-exposed (PE) children develop alterations in heart rate variability (HRV) and if this is reflected in their blood pressure (BP), as well as overall associations with body size and composition, gestational and perinatal factors. We examined 182 PE (46 early-onset PE) and 85 unexposed (non-PE) children 8-12 yr after preeclampsia exposure. HRV monitoring was performed 5 min in supine followed... -
Positive maternal mental health during pregnancy and psychiatric problems in children from early childhood to late childhood
Negative maternal mental health during pregnancy increases the risk of psychiatric problems in children, but research on the potential benefits of positive maternal mental health during pregnancy is scarce. We investigated associations between positive maternal mental health composite score, based on reports of maternal positive affect, curiosity, and social support during pregnancy, and children's psychiatric problems (Child Behavior Checklist) at ages 1.9-5.9 and 7.1-12.1 years among 2636... -
Etiology of intracerebral hemorrhage during pregnancy or puerperium: A nationwide study
CONCLUSIONS: Even in a country with a comprehensive pregnancy surveillance system, the maternal mortality rate for pICH is high, and the sequelae are severe. Early recognition and treatment of the key risk factor, HDP, is crucial to help prevent this serious pregnancy complication.
2023
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Lifestyle-based and psychological interventions during pregnancy and risk of obesity and obesity-associated metabolic complications in the offspring: A scoping review
CONCLUSIONS: A limited number of studies have evaluated offspring outcomes beyond the neonatal period. Lifestyle-based interventions including psychological components are particularly scarce. The research conducted demonstrated only a minor impact on childhood anthropometric and metabolic outcomes; however, the interpretation of these findings is hampered by a considerable risk of bias, largely due to missing offspring data. -
Monoallelic TYROBP deletion is a novel risk factor for Alzheimer's disease
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population... -
Validation of the Finnish Care register for Health Care diagnoses for preeclampsia, gestational diabetes and preterm delivery
CONCLUSIONS: FCR registry diagnoses for PE have satisfactory sensitivity and high specificity. Diagnoses for GDM and preterm delivery have lower sensitivity limiting their use in studies, and data from MBR should be preferred when studying preterm deliveries. -
Costs of abduction treatment in developmental dysplasia of the hip. Analysis of 900 patients
CONCLUSION: With correct patient selection, a watchful waiting strategy is cost-effective in treating mild developmental dysplasia of the hip, considering the high percentage of spontaneous recovery. -
NTHL1 is a recessive cancer susceptibility gene
In search of novel breast cancer (BC) risk variants, we performed a whole-exome sequencing and variant analysis of 69 Finnish BC patients as well as analysed loss-of-function variants identified in DNA repair genes in the Finns from the Genome Aggregation Database. Additionally, we carried out a validation study of SERPINA3 c.918-1G>C, recently suggested for BC predisposition. We estimated the frequencies of 41 rare candidate variants in 38 genes by genotyping them in 2482-4101 BC patients and... -
Endometrial preparation protocols prior to frozen embryo transfer - convenience or safety?
The number of frozen embryo transfer (FET) cycles is increasing rapidly worldwide. Different endometrial preparations for FET result in comparable live birth rates. However, several recent publications have reported higher maternal risks for hypertensive disorders of pregnancy (HDP), pre-eclampsia and postpartum haemorrhage (PPH) in programmed cycles (PC-FET) compared with natural cycles and modified natural cycles with an intact corpus luteum. Nevertheless, PC-FET is frequently used in... -
Preeclampsia-exposed children's heart rate variability 8-12 yr after index pregnancy: FINNCARE study
Preeclampsia is related with elevated systolic blood pressure (SBP) in children. We studied if preeclampsia-exposed (PE) children develop alterations in heart rate variability (HRV) and if this is reflected in their blood pressure (BP), as well as overall associations with body size and composition, gestational and perinatal factors. We examined 182 PE (46 early-onset PE) and 85 unexposed (non-PE) children 8-12 yr after preeclampsia exposure. HRV monitoring was performed 5 min in supine followed... -
Meta-analysis of genome-wide association studies of gestational duration and spontaneous preterm birth identifies new maternal risk loci
CONCLUSION: We report novel genetic risk loci that associate with preterm birth or gestational duration, and reproduce findings from previous genome-wide association studies. Altogether, our findings provide new insight into the genetic background of preterm birth. Better characterization of the causal genetic mechanisms will be important to public health as it could suggest new strategies to treat and prevent preterm birth. -
Determinants of vascular structure and function in at-risk children born to mothers managed for pre-eclampsia (FINNCARE study)
CONCLUSIONS: The peripheral artery IMT of PE-exposed children is identical to that of non-PE-exposed children, but associated with BP. Adiposity is related to local carotid artery stiffness. These adverse associations in arterial health may reflect the early progression of cardiovascular disease in PE-exposed children. -
Positive maternal mental health during pregnancy and psychiatric problems in children from early childhood to late childhood
Negative maternal mental health during pregnancy increases the risk of psychiatric problems in children, but research on the potential benefits of positive maternal mental health during pregnancy is scarce. We investigated associations between positive maternal mental health composite score, based on reports of maternal positive affect, curiosity, and social support during pregnancy, and children's psychiatric problems (Child Behavior Checklist) at ages 1.9-5.9 and 7.1-12.1 years among 2636... -
Gestational diabetes is associated with the risk of offspring's congenital anomalies: a register-based cohort study
CONCLUSIONS: Offspring exposed to GDM have a higher prevalence of major CAs. Of note, risk factors other than GDM, such as older maternal age and a higher pre-pregnancy BMI, diminished the between group differences in the prevalence of major CAs. Nevertheless, our findings suggest that offspring exposed to maternal GDM are more likely to be diagnosed with a chromosomal abnormality, independent of maternal age, parity, pre-pregnancy BMI, and smoking. -
Hypertensive pregnancy complications and maternal characteristics as predictors of cardiovascular health within ten years after delivery
CONCLUSIONS: Healthcare professionals should target early prevention of CVDs in women with chronic hypertension during pregnancy; of those who developed superimposed PE prior to 34th weeks of gestation and who delivered preterm. Women with de novo PE who are overweight/obese, primiparous, and with concurrent GDM need regular blood pressure monitoring. -
Use of electronic health record data mining for heart failure subtyping
OBJECTIVE: To assess whether electronic health record (EHR) data text mining can be used to improve register-based heart failure (HF) subtyping. EHR data of 43,405 individuals from two Finnish hospital biobanks were mined for unstructured text mentions of ejection fraction (EF) and validated against clinical assessment in two sets of 100 randomly selected individuals. Structured laboratory data was then incorporated for a categorization by HF subtype (HF with mildly reduced EF, HFmrEF; HF with... -
Pregnancy-Associated Bleeding and Genetics: Five Sequence Variants in the Myometrium and Progesterone Signaling Pathway are associated with postpartum hemorrhage
Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severity of these complications in maternal-fetal health. Here, we investigated the genetic variation underlying aspects of pregnancy-associated bleeding and identified five loci associated with PPH through a meta-analysis of 21,512 cases and 259,500 controls. Functional annotation... -
Serum ceramides in early pregnancy as predictors of gestational diabetes
Ceramides contribute to the development of type 2 diabetes but it is uncertain whether they predict gestational diabetes (GDM). In this multicentre case-control study including 1040 women with GDM and 958 non-diabetic controls, early pregnancy (mean 10.7 gestational weeks) concentrations of four ceramides-Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)-were determined by a validated mass-spectrometric method from biobanked serum samples. Traditional lipids including total... -
A FinnGen pilot clinical recall study for Alzheimer's disease
Successful development of novel therapies requires that clinical trials are conducted in patient cohorts with the highest benefit-to-risk ratio. Population-based biobanks with comprehensive health and genetic data from large numbers of individuals hold promise to facilitate identification of trial participants, particularly when interventions need to start while symptoms are still mild, such as for Alzheimer's disease (AD). This study describes a process for clinical recall studies from FinnGen.... -
Etiology of intracerebral hemorrhage during pregnancy or puerperium: A nationwide study
CONCLUSIONS: Even in a country with a comprehensive pregnancy surveillance system, the maternal mortality rate for pICH is high, and the sequelae are severe. Early recognition and treatment of the key risk factor, HDP, is crucial to help prevent this serious pregnancy complication. -
Data Resource Profile: Nationwide registry data for high-throughput epidemiology and machine learning (FinRegistry)
No abstract -
Blood pressure, arterial stiffness, and cardiovascular risk profiles in 8-12-year-old children following preeclampsia (FINNCARE-study)
CONCLUSIONS: PE children develop an adverse BP profile and arterial stiffness early in life. PE-related BP is related with maternal gestational BP and prematurity, whereas arterial stiffness is determined by child characteristics at follow-up. The alterations in BP are pronounced in early-onset PE.Clinical Trial Registration information: https://clinicaltrials.gov/ct2/show/NCT04676295ClinicalTrials.gov Identifier: NCT04676295. -
Major Genetic Risk Factors for Dupuytren's Disease Are Inherited From Neandertals
Dupuytren's disease is characterized by fingers becoming permanently bent in a flexed position. Whereas people of African ancestry are rarely afflicted by Dupuytren's disease, up to ∼30% of men over 60 years suffer from this condition in northern Europe. Here, we meta-analyze 3 biobanks comprising 7,871 cases and 645,880 controls and find 61 genome-wide significant variants associated with Dupuytren's disease. We show that 3 of the 61 loci harbor alleles of Neandertal origin, including the... -
The public health impact of poor sleep on severe COVID-19, influenza and upper respiratory infections
BACKGROUND: Poor sleep is associated with an increased risk of infections and all-cause mortality but the causal direction between poor sleep and respiratory infections has remained unclear. We examined if poor sleep contributes as a causal risk factor to respiratory infections. -
Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy
CONCLUSIONS AND RELEVANCE: The findings indicate that genes related to blood pressure traits are associated with preeclampsia, but many of these genes have additional pleiotropic effects on cardiometabolic, endothelial, and placental function. Furthermore, several of the associated loci have no known connection with cardiovascular disease but instead harbor genes contributing to maintenance of successful pregnancy, with dysfunctions leading to preeclampsialike symptoms. -
Etiology and risk factors of ischemic stroke during pregnancy and puerperium: A population-based study
INTRODUCTION: Ischemic stroke (IS) is an uncommon, but potentially life-changing, complication of pregnancy. The aim of this study was to analyze the etiology and risk factors of pregnancy-associated IS. -
Metabolomic Profiles of Nonobese and Obese Women With Gestational Diabetes
CONCLUSION: Differences between nonobese and obese GDM, or obese non-GDM women and controls in metabolomic profiles may allow detection of high-risk women for timely targeted preventive interventions. -
Risk of Midlife Stroke After Adverse Pregnancy Outcomes: The FinnGen Study
CONCLUSIONS: Women who experience APO have earlier onset of cerebrovascular disease, with the earliest onset in those with more than 1 affected pregnancy. -
Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy
Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant... -
Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study
CONCLUSIONS: These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre-eclampsia. -
Pregnancy-associated stroke and the recurrence of stroke and other complications in subsequent pregnancies: Population-based retrospective cohort study
CONCLUSIONS: Subsequent pregnancies of women with a history of PAS are more often complicated with hypertensive disorders of pregnancy and any diabetes during pregnancy. PAS recurrence risk is considerable. -
Known risk factors of the developmental dysplasia of the hip predicting more severe clinical presentation and failure of Pavlik harness treatment
CONCLUSION: Breech presentation seems to increase the risk of Ortolani positive DDH. However, these infants are likely to recover with initially started Pavlik harness treatment, as it was not associated with elevated risk for undergoing more robust treatments. Positive family history and girl sex are associated with the most severe cases of developmental dysplasia of the hip, and it may predispose to the failure of the Pavlik harness treatment. -
Associations of polygenic risk scores for preeclampsia and blood pressure with hypertensive disorders of pregnancy
CONCLUSION: BP-PRS is strongly associated with hypertensive disorders of pregnancy. Our current observations suggest that the BP-PRS could capture the genetic architecture of preeclampsia better than the current PE-PRSs. These findings also emphasize the common pathways in the development of all BP disorders. The clinical utility of a BP-PRS for preeclampsia prediction warrants further investigation. -
GWAS meta-analyses clarify the genetics of cervical phenotypes and inform risk stratification for cervical cancer
Genome-wide association studies (GWAS) have successfully identified associations for cervical cancer, but the underlying mechanisms of cervical biology and pathology remain uncharacterised. Our GWAS meta-analyses fill this gap, as we characterise the genetic architecture of cervical phenotypes, including cervical ectropion, cervicitis, cervical dysplasia, as well as up to 9229 cases and 490 304 controls for cervical cancer from diverse ancestries. Leveraging the latest computational methods and... -
The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions
Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes... -
Author Correction: FinnGen provides genetic insights from a well-phenotyped isolated population
No abstract -
Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies.... -
FinnGen provides genetic insights from a well-phenotyped isolated population
Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored^(1,2). FinnGen aims to study the genome and national... -
Associations of low sex hormone-binding globulin and androgen excess in early pregnancy with fasting and post-prandial hyperglycaemia, gestational diabetes, and its severity
CONCLUSIONS: Lower SHBG levels were associated especially with early-onset GDM, higher fasting glucose and insulin treatment, whereas androgen excess was associated with higher post-prandial glucose values. Thus, a low SHBG level may reflect the degree of existing insulin resistance, while androgen excess might impair post-prandial insulin secretion. -
Subarachnoid Hemorrhage During Pregnancy and Puerperium: A Population-Based Study
CONCLUSIONS: The incidence of pSAH has not changed substantially over time in Finland. The majority of pSAH cases were aneurysmal and women with aneurysm had considerable mortality and morbidity. Counseling of pregnant women about smoking cessation and monitoring of blood pressure and symptoms of pre-eclampsia are important interventions to prevent pSAH. -
Maternal exposure to childhood maltreatment and mental and behavioral disorders in children
Exposure to maltreatment in childhood is associated with lifelong risk of mental and behavioral disorders. Whether the effects extend to the next generation remains unclear. We examined whether maternal exposure to childhood abuse and neglect in her own childhood were associated with mental and behavioral disorders and psychiatric symptoms in her children, and whether maternal lifetime mental and behavioral disorders or lower education level mediated or added to the effects. Mothers (n = 2252)... -
Birth injury in breech delivery: a nationwide population-based cohort study in Finland
CONCLUSION: Birth injuries were rare in vaginal breech deliveries. The incidence of severe birth injury was two times higher in vaginal breech delivery compared to cephalic vaginal delivery. Brachial plexus palsy was the most common type of injury in vaginal breech delivery. -
Incidence changes in risk factors associated with the decreasing number of birth-related clavicle fractures in Finland: A nationwide retrospective birth cohort from 2004 to 2017
BACKGROUND: A clavicle fracture is one of the most common birth injuries. The objective of this study was to examine whether the decreased incidence of birth-related clavicle fractures in Finland is because of temporal changes in their predisposing factors. -
Positive maternal mental health during pregnancy and mental and behavioral disorders in children: A prospective pregnancy cohort study
CONCLUSIONS: Children whose mothers had more positive mental health during pregnancy were less likely to develop mental and behavioral disorders. Protective effects were seen also among children of mothers facing mental health adversities before or during pregnancy.
2022
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Cohort profile update: the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC)
PURPOSE: The Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) study was originally established between 2008 and 2011 to develop a nationwide clinical and genomic database. By enrolling women with and without pre-eclampsia (PE), alongside their partners and infants, the study aims to identify the genetic and molecular determinants of PE. This update summarises the final dataset, reviews key findings since the 2016 cohort profile, and outlines current research directions. -
A Population-Based Study of Posterior Reversible Encephalopathy Syndrome and Reversible Cerebral Vasoconstriction Syndrome During Pregnancy and Puerperium
CONCLUSIONS: Pregnancy-associated PRES and RCVS are potentially life-threatening, rare conditions that can result in hemorrhagic stroke. PRES ± RCVS is strongly associated with preeclampsia with severe features, whereas puerperal RCVS seems to be a separate, later-occurring condition. -
Long-Term Recovery, Morbidity, and Mortality After Maternal Ischemic Stroke
BACKGROUND AND OBJECTIVES: The long-term prognosis after maternal ischemic stroke (IS) remains understudied. The objectives were to examine if mortality and long-term morbidity are more frequent in women with prior maternal IS compared with women without a pregnancy-related stroke and to assess recovery in maternal IS patients based on functional outcomes and vocational status. -
Monoallelic TYROBP deletion is a novel risk factor for Alzheimer's disease
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population... -
Narcolepsy as a potential risk factor for Schizophrenia
Narcolepsy is a severe sleep disorder with characteristics of fatigue, fragmented sleep, cataplexy and hypnagogic hallucinations. Earlier clinical studies have reported the onset of schizophrenia after narcolepsy but the causality behind narcolepsy and schizophrenia is unknown. Our goal was to understand the causality between narcolepsy and schizophrenia. To estimate the comorbidity between narcolepsy and schizophrenia, we employed data from the FinRegistry that contains data for the total... -
Metabolic profiles of meconium in preeclamptic and normotensive pregnancies
CONCLUSION: PE is associated with alterations in the meconium metabolome of infants. The differing abundances of several metabolites show alterations in the interaction between the fetoplacental unit and mother in PE, but whether they are a cause or an effect of the disorder remains to be further investigated. -
Long-Term Mortality, Recovery, and Vocational Status After a Maternal Stroke: Register-Based Observational Case-Control Study
BACKGROUND AND OBJECTIVES: Maternal stroke is a rare event with an increasing incidence. Data on the long-term prognosis after a maternal stroke are limited. We aimed to examine long-term mortality, recovery, vocational status and morbidity after a maternal stroke in a population-based setting including a comparison with matched, stroke-free controls. -
TWINGEN: protocol for an observational clinical biobank recall and biomarker cohort study to identify Finnish individuals with high risk of Alzheimer's disease
INTRODUCTION: A better understanding of the earliest stages of Alzheimer's disease (AD) could expedite the development or administration of treatments. Large population biobanks hold the promise to identify individuals at an elevated risk of AD and related dementias based on health registry information. Here, we establish the protocol for an observational clinical recall and biomarker study called TWINGEN with the aim to identify individuals at high risk of AD by assessing cognition, health and... -
Associations of polygenic risk scores for preeclampsia and blood pressure with hypertensive disorders of pregnancy
CONCLUSION: BP-PRS is strongly associated with hypertensive disorders of pregnancy. Our current observations suggest that the BP-PRS could capture the genetic architecture of preeclampsia better than the current PE-PRSs. These findings also emphasize the common pathways in the development of all BP disorders. The clinical utility of a BP-PRS for preeclampsia prediction warrants further investigation. -
Optimized detection of homologous recombination deficiency improves the prediction of clinical outcomes in cancer
Homologous recombination DNA-repair deficiency (HRD) is a common driver of genomic instability and confers a therapeutic vulnerability in cancer. The accurate detection of somatic allelic imbalances (AIs) has been limited by methods focused on BRCA1/2 mutations and using mixtures of cancer types. Using pan-cancer data, we revealed distinct patterns of AIs in high-grade serous ovarian cancer (HGSC). We used machine learning and statistics to generate improved criteria to identify HRD in HGSC... -
Effects of race and ethnicity on perinatal outcomes in high-income and upper-middle-income countries: an individual participant data meta-analysis of 2 198 655 pregnancies
BACKGROUND: Existing evidence on the effects of race and ethnicity on pregnancy outcomes is restricted to individual studies done within specific countries and health systems. We aimed to assess the impact of race and ethnicity on perinatal outcomes in high-income and upper-middle-income countries, and to ascertain whether the magnitude of disparities, if any, varied across geographical regions. -
Clinical and sonographic improvement of developmental dysplasia of the hip: analysis of 948 patients
CONCLUSION: Female sex and positive family history might be independent risk factors for slower recovery in DDH before 6 months of age. These children might need special attention in their follow-up plans and abduction treatment. -
Associations of low sex hormone-binding globulin and androgen excess in early pregnancy with fasting and post-prandial hyperglycaemia, gestational diabetes, and its severity
CONCLUSIONS: Lower SHBG levels were associated especially with early-onset GDM, higher fasting glucose and insulin treatment, whereas androgen excess was associated with higher post-prandial glucose values. Thus, a low SHBG level may reflect the degree of existing insulin resistance, while androgen excess might impair post-prandial insulin secretion. -
Subarachnoid Hemorrhage During Pregnancy and Puerperium: A Population-Based Study
CONCLUSIONS: The incidence of pSAH has not changed substantially over time in Finland. The majority of pSAH cases were aneurysmal and women with aneurysm had considerable mortality and morbidity. Counseling of pregnant women about smoking cessation and monitoring of blood pressure and symptoms of pre-eclampsia are important interventions to prevent pSAH. -
Genome-Wide Copy Number Variant and High-Throughput Transcriptomics Analyses of Placental Tissues Underscore Persisting Child Susceptibility in At-Risk Pregnancies Cleared in Standard Genetic Testing
Several studies have shown that children from pregnancies with estimated first-trimester risk based on fetal nuchal translucency thickness and abnormal maternal serum pregnancy protein and hormone levels maintain a higher likelihood of adverse outcomes, even if initial testing for known genetic conditions is negative. We used the Finnish InTraUterine cohort (ITU), which is a comprehensively characterized perinatal cohort consisting of 943 mothers and their babies followed throughout pregnancy... -
Recontacting biobank participants to collect lifestyle, behavioural and cognitive information via online questionnaires: lessons from a pilot study within FinnGen
CONCLUSION: In summary, this pilot suggests that recontacting FinnGen participants with the goal to collect a wide range of cognitive, behavioural and lifestyle information without additional engagement results in a low participation rate, but with reliable data. We suggest that such information be collected at enrolment, if possible, rather than via post hoc recontacting. -
Maternal exposure to childhood maltreatment and mental and behavioral disorders in children
Exposure to maltreatment in childhood is associated with lifelong risk of mental and behavioral disorders. Whether the effects extend to the next generation remains unclear. We examined whether maternal exposure to childhood abuse and neglect in her own childhood were associated with mental and behavioral disorders and psychiatric symptoms in her children, and whether maternal lifetime mental and behavioral disorders or lower education level mediated or added to the effects. Mothers (n = 2252)... -
Increased Oral Care Needs and Third Molar Symptoms in Women with Gestational Diabetes Mellitus: A Finnish Gestational Diabetes Case-Control Study
(1) Hyperglycemia and oral pathology accelerate each other in diabetes. We evaluated whether gestational diabetes mellitus (GDM) is associated with self-reported increased oral health care needs and oral symptoms, including third molar symptoms, during pregnancy. (2) Pregnant women with (n = 1030) and without GDM (n = 935) were recruited in this multicenter Finnish Gestational Diabetes study in 2009-2012. Of the women with GDM, 196 (19.0%) receiving pharmacological treatment, 797 (77.0%)... -
Birth injury in breech delivery: a nationwide population-based cohort study in Finland
CONCLUSION: Birth injuries were rare in vaginal breech deliveries. The incidence of severe birth injury was two times higher in vaginal breech delivery compared to cephalic vaginal delivery. Brachial plexus palsy was the most common type of injury in vaginal breech delivery. -
Inframe insertion and splice site variants in MFGE8 associate with protection against coronary atherosclerosis
Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finland's population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for... -
Maternal early-pregnancy body mass index-associated metabolomic component and mental and behavioral disorders in children
Maternal pre-pregnancy obesity and/or higher body mass index (BMI) have been associated with neurodevelopmental and mental health adversities in children. While maternal metabolomic perturbations during pregnancy may underpin these associations, the existing evidence is limited to studying individual metabolites, not capturing metabolic variation specific to maternal BMI, and not accounting for the correlated nature of the metabolomic measures. By using multivariate supervised analytical... -
Increased Risk of Preeclampsia in Women With a Genetic Predisposition to Elevated Blood Pressure
CONCLUSIONS: Our results suggest that HBP-PRS is associated with an increased risk of preeclampsia, recurrent preeclampsia, and preeclampsia with severe features. Furthermore, women with HBP-PRS present higher BP values during pregnancy. The results strengthen the evidence pointing toward the role of genetic variants associated with BP regulation in the etiology of preeclampsia, especially its more severe forms. -
Incidence changes in risk factors associated with the decreasing number of birth-related clavicle fractures in Finland: A nationwide retrospective birth cohort from 2004 to 2017
BACKGROUND: A clavicle fracture is one of the most common birth injuries. The objective of this study was to examine whether the decreased incidence of birth-related clavicle fractures in Finland is because of temporal changes in their predisposing factors. -
Positive maternal mental health during pregnancy and mental and behavioral disorders in children: A prospective pregnancy cohort study
CONCLUSIONS: Children whose mothers had more positive mental health during pregnancy were less likely to develop mental and behavioral disorders. Protective effects were seen also among children of mothers facing mental health adversities before or during pregnancy. -
Genetic risk of type 2 diabetes modifies the effects of a lifestyle intervention aimed at the prevention of gestational and postpartum diabetes
CONCLUSIONS/INTERPRETATION: Genetic predisposition to diabetes modifies the response to a lifestyle intervention aimed at prevention of GDM and postpartum diabetes. This suggests that lifestyle intervention may benefit from being tailored according to genetic risk. -
Circulating Levels of Anti-C1q and Anti-Factor H Autoantibodies and Their Targets in Normal Pregnancy and Preeclampsia
Preeclampsia (PE) generally manifests in the second half of pregnancy with hypertension and proteinuria. The understanding of the origin and mechanism behind PE is incomplete, although there is clearly an immune component to this disorder. The placenta constitutes a complicated immune interface between fetal and maternal cells, where regulation and tolerance are key. Stress factors from placental dysfunction in PE are released to the maternal circulation evoking the maternal response. Several... -
New insights into the genetic etiology of Alzheimer's disease and related dementias
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted... -
No association in maternal serum levels of TMAO and its precursors in pre-eclampsia and in non-complicated pregnancies
Only a few studies have explored the role of microbiota-dependent metabolite trimethylamine N-oxide (TMAO) in non-complicated pregnancy and in pre-eclampsia (PE). We enrolled 139 PE and 29 healthy pregnant women in a nested case control study. We hypothesized that elevated levels of circulating TMAO and its precursors choline and glycine betaine in the late second or in third trimester might contribute to the PE and are associated with the onset of the disease and clinical features such as... -
Protocol: A randomized controlled trial to assess effectiveness of a 12-month lifestyle intervention to reduce cardiovascular disease risk in families ten years after pre-eclampsia (FINNCARE)
Pre-eclampsia (PE) is a multisystem progressive disorder affecting 3-5% of pregnancies. PE independently increases the risk for premature cardiovascular disease (CVD) in mothers and their children long-term. The effectiveness of a family-centered lifestyle intervention to lower CVD risk in PE families has not previously been evaluated. In the current FINNCARE study, we prospectively compare CVD risk and CVD progression in PE families (mother, father and child) in a cross-sectional study setting... -
Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes
Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association... -
Integration of questionnaire-based risk factors improves polygenic risk scores for human coronary heart disease and type 2 diabetes
Large-scale biobank initiatives and commercial repositories store genomic data collected from millions of individuals, and tools to leverage the rapidly growing pool of health and genomic data in disease prevention are needed. Here, we describe the derivation and validation of genomics-enhanced risk tools for two common cardiometabolic diseases, coronary heart disease and type 2 diabetes. Data used for our analyses include the FinnGen study (N = 309,154) and the UK Biobank project (N = 343,672).... -
Reliability of a novel approach for reference-based cell type estimation in human placental DNA methylation studies
The placenta is a central organ during early development, influencing trajectories of health and disease. DNA methylation (DNAm) studies of human placenta improve our understanding of how its function relates to disease risk. However, DNAm studies can be biased by cell type heterogeneity, so it is essential to control for this in order to reduce confounding and increase precision. Computational cell type deconvolution approaches have proven to be very useful for this purpose. For human placenta,... -
Cohort profile: InTraUterine sampling in early pregnancy (ITU), a prospective pregnancy cohort study in Finland: study design and baseline characteristics
PURPOSE: The InTraUterine sampling in early pregnancy (ITU) is a prospective pregnancy cohort study. The overarching aim of ITU is to unravel genomic, epigenomic, transcriptomic, endocrine, inflammatory and metabolic maternal-placental-fetal mechanisms involved in the programming of health and disease after exposure to prenatal environmental adversity, such as maternal malnutrition, cardiometabolic disorders, infections, medical interventions, mental disorders and psychosocial stress. This paper... -
Maternal postpartum depressive symptoms partially mediate the association between preterm birth and mental and behavioral disorders in children
Preterm birth has been linked with postpartum depressive (PPD) disorders and high symptom levels, but evidence remains conflicting and limited in quality. It remains unclear whether PPD symptoms of mothers with preterm babies were already elevated before childbirth, and whether PPD symptoms mediate/aggravate the effect of preterm birth on child mental disorders. We examined whether preterm birth associated with maternal PPD symptoms, depressive symptoms trajectories from antenatal to postpartum... -
Severe birth injuries in neonates and associated risk factors for injury in mothers with different types of diabetes in Finland
CONCLUSION: Neonates of women with pregestational diabetes have a higher risk for severe birth injury than other neonates. The injury risk in neonates delivered by women with gestational diabetes or non-diabetic women is generally low. -
Characteristics of preeclampsia in donor cell gestations
Pregnancies conceived through donor oocytes or sperm show increased risk for preeclampsia. We studied this issue in a preeclampsia case-control cohort (n = 2778), and found overrepresentation of donor cell gestations among women with preeclampsia (14/1627, 0.86%; OR 1.81; 95% CI: 1.07-3.08; P = 0.025) compared to the population data. Moreover, we observed excess of male births from donor cell pregnancies (male-to-female ratio 2.5 vs. 0.97; OR 2.57; 95% CI 1.02-6.36; P = 0.043). Maternal age... -
Multiomics and digital monitoring during lifestyle changes reveal independent dimensions of human biology and health
We explored opportunities for personalized and predictive health care by collecting serial clinical measurements, health surveys, genomics, proteomics, autoantibodies, metabolomics, and gut microbiome data from 96 individuals who participated in a data-driven health coaching program over a 16-month period with continuous digital monitoring of activity and sleep. We generated a resource of >20,000 biological samples from this study and a compendium of >53 million primary data points for 558,032... -
Leveraging Northern European population history: novel low-frequency variants for polycystic ovary syndrome
STUDY QUESTION: Can we identify novel variants associated with polycystic ovary syndrome (PCOS) by leveraging the unique population history of Northern Europe? -
Routine Bedside Use of Obstetric Early Warning System in the Postnatal Ward to Identify Maternal Morbidity Among High-Risk Women
CONCLUSIONS: In high-risk women, OEWS revealed one-half of the morbidity. Women with PPH and preeclampsia benefited most from it. Abnormal blood pressure and pulse had the strongest associations with morbidity.
2021
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Monoallelic TYROBP deletion is a novel risk factor for Alzheimer's disease
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population... -
Narcolepsy as a potential risk factor for Schizophrenia
Narcolepsy is a severe sleep disorder with characteristics of fatigue, fragmented sleep, cataplexy and hypnagogic hallucinations. Earlier clinical studies have reported the onset of schizophrenia after narcolepsy but the causality behind narcolepsy and schizophrenia is unknown. Our goal was to understand the causality between narcolepsy and schizophrenia. To estimate the comorbidity between narcolepsy and schizophrenia, we employed data from the FinRegistry that contains data for the total... -
Sex-specific genetic risks for adverse outcomes after coronary revascularization procedures
Men and women have differing risks of adverse events after revascularization procedures and these differences could be partially driven by genetics. We studied the sex-specific differences in associations of polygenic risk scores (PRSs) with atrial fibrillation (AF), ischaemic stroke (STR), intracranial haemorrhage (ICH), myocardial infarction (MI) and gastrointestinal haemorrhage (GIH) in coronary revascularization patients. The study cohort comprised 5561 and 17 578 revascularized women and... -
Associations of polygenic risk scores for preeclampsia and blood pressure with hypertensive disorders of pregnancy
CONCLUSION: BP-PRS is strongly associated with hypertensive disorders of pregnancy. Our current observations suggest that the BP-PRS could capture the genetic architecture of preeclampsia better than the current PE-PRSs. These findings also emphasize the common pathways in the development of all BP disorders. The clinical utility of a BP-PRS for preeclampsia prediction warrants further investigation. -
Recontacting biobank participants to collect lifestyle, behavioural and cognitive information via online questionnaires: lessons from a pilot study within FinnGen
CONCLUSION: In summary, this pilot suggests that recontacting FinnGen participants with the goal to collect a wide range of cognitive, behavioural and lifestyle information without additional engagement results in a low participation rate, but with reliable data. We suggest that such information be collected at enrolment, if possible, rather than via post hoc recontacting. -
New insights into the genetic etiology of Alzheimer's disease and related dementias
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted... -
Characteristics of preeclampsia in donor cell gestations
Pregnancies conceived through donor oocytes or sperm show increased risk for preeclampsia. We studied this issue in a preeclampsia case-control cohort (n = 2778), and found overrepresentation of donor cell gestations among women with preeclampsia (14/1627, 0.86%; OR 1.81; 95% CI: 1.07-3.08; P = 0.025) compared to the population data. Moreover, we observed excess of male births from donor cell pregnancies (male-to-female ratio 2.5 vs. 0.97; OR 2.57; 95% CI 1.02-6.36; P = 0.043). Maternal age... -
Multiomics and digital monitoring during lifestyle changes reveal independent dimensions of human biology and health
We explored opportunities for personalized and predictive health care by collecting serial clinical measurements, health surveys, genomics, proteomics, autoantibodies, metabolomics, and gut microbiome data from 96 individuals who participated in a data-driven health coaching program over a 16-month period with continuous digital monitoring of activity and sleep. We generated a resource of >20,000 biological samples from this study and a compendium of >53 million primary data points for 558,032... -
Betamethasone administration during pregnancy is associated with placental epigenetic changes with implications for inflammation
CONCLUSIONS: Our findings suggest that BET exposure during pregnancy associates with few but lasting changes in placental DNAm and may promote a gene expression profile associated with placental dysfunction and increased inflammation. This may represent a pathway mediating GC-associated negative long-term consequences and health outcomes in offspring. -
Lifetime risk of rheumatoid arthritis-associated interstitial lung disease in <em>MUC5B</em> mutation carriers
CONCLUSION: Our findings provide estimates of lifetime risk of RA-ILD based on MUC5B mutation carrier status, demonstrating the potential of genomics for risk stratification of RA-ILD. -
The Association Between High Birth Weight and Long-Term Outcomes-Implications for Assisted Reproductive Technologies: A Systematic Review and Meta-Analysis
Background: Studies have shown that the prevalence of children born with high birth weight or large for gestational age (LGA) is increasing. This is true for spontaneous pregnancies; however, children born after frozen embryo transfer (FET) as part of assisted reproductive technology (ART) also have an elevated risk. In recent years, the practice of FET has increased rapidly and while the perinatal and obstetric risks are well-studied, less is known about the long-term health consequences.... -
Longitudinal Metabolic Profiling of Maternal Obesity, Gestational Diabetes, and Hypertensive Pregnancy Disorders
CONCLUSIONS: This study shows that the pregnancy-related metabolic change is smaller in women with obesity, who display metabolic perturbations already in early pregnancy. Metabolic alterations of obesity and pregnancy disorders resembled each other suggesting a shared metabolic origin. -
Normal Gestational Weight Gain Protects From Large-for-Gestational-Age Birth Among Women With Obesity and Gestational Diabetes
Background: Pre-pregnancy obesity, excess gestational weight gain (GWG), and gestational diabetes (GDM) increase fetal growth. Our aim was to assess whether normal GWG is associated with lower risk for a large-for-gestational-age (LGA; over the 90th percentile of birth weight for sex and gestational age) infant and lower birth weight standard deviation (SD) score in the presence of GDM and maternal obesity. Methods: This multicenter case-control study is part of the Finnish Gestational Diabetes... -
Serum Inhibin-A and PAPP-A2 in the prediction of pre-eclampsia during the first and second trimesters in high-risk women
CONCLUSIONS: At first trimester inhibin-A show potential ability to predict not only EO PE but also LO PE whereas PlGF and PAPP-A predict only EO PE. At late second trimester inhibin-A and PAPP-A2 might be useful for short-term prediction of PE. -
Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection
Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from... -
Association of the MYOC p.(Gln368Ter) Variant With Glaucoma in a Finnish Population
CONCLUSIONS AND RELEVANCE: This genetic association study found that the MYOC p.(Gln368Ter) variant was associated with exfoliation glaucoma. The association with normal-tension glaucoma could not be replicated. These findings suggest that MYOC p.(Gln368Ter) was associated with open-angle glaucoma and exfoliation glaucoma in a Finnish population. -
A systematic review and meta-analysis on the association between ICSI and chromosome abnormalities
BACKGROUND: In the decade following the introduction of ICSI, a higher prevalence of de novo chromosome abnormalities, in particular sex chromosome and autosomal structural abnormalities, as well as inherited abnormalities was described in children conceived by ICSI compared to both naturally conceived (NC) children and children conceived by standard IVF. The explanation for the observed increase in prevalence is not clear and has been suggested to reflect parental factors (e.g. age or sperm... -
Characteristics of epigenetic aging across gestational and perinatal tissues
CONCLUSION: Gestational epigenetic age acceleration or deceleration was not related to more favorable or unfavorable factors in one direction in the investigated tissues, and the relative epigenetic age differed between tissues of the same person. This indicates that epigenetic age deviations associate with distinct, tissue specific, factors during the gestational and perinatal period. Our findings suggest that the epigenetic age of the newborn should be seen as a characteristic of a specific... -
Obstetric early warning system to predict maternal morbidity of pre-eclampsia, postpartum hemorrhage and infection after birth in high-risk women: a prospective cohort study
OBJECTIVE: The purpose of early warning systems is to detect deterioration of the patient and to enable timely intervention to prevent possible severe illness. The most common causes of maternal morbidity and mortality after birth are worsening pre-eclampsia, postpartum haemorrhage and puerperal infection. Our aim was to validate the accuracy of the obstetric early warning system and different physiological triggers to predict morbidity on the postnatal ward in high-risk women. -
Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices
Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL... -
Stroke in Pregnancy and Puerperium: Validated Incidence Trends With Risk Factor Analysis in Finland 1987-2016
CONCLUSION: PAS incidence is increasing, stressing the importance of careful pregnancy surveillance and risk factor management, particularly in older expectant mothers and extending to puerperium. -
Angiogenic Effect of Pravastatin Alone and with Sera from Healthy and Complicated Pregnancies Studied by in vitro Vasculogenesis/Angiogenesis Assay
CONCLUSIONS: At therapeutic concentration, pravastatin alone or with maternal sera has no significant effect on angiogenesis, but at high concentrations the effect seems to be anti-angiogenic estimated by in vitro assay. -
Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia: a genetic and functional study
CONCLUSIONS: Results suggest that changes in complement-facilitated phagocytosis are associated with pre-eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro- and anti-inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre-eclampsia pathogenesis. -
A non-targeted LC-MS metabolic profiling of pregnancy: longitudinal evidence from healthy and pre-eclamptic pregnancies
CONCLUSIONS: Our study highlights the need of large-scale longitudinal metabolomic studies in non-complicated pregnancies before more detailed understanding of metabolism in adverse outcomes could be provided. Our findings are one of the first steps for a broader metabolic understanding of the physiological changes caused by pregnancy per se. -
Sleep apnoea is a risk factor for severe COVID-19
CONCLUSION: Risk for contracting COVID-19 was the same for patients with OSA and those without OSA. In contrast, among COVID-19 positive patients, OSA was associated with higher risk for hospitalisation. Our findings are in line with earlier works and suggest OSA as an independent risk factor for severe COVID-19. -
The non-traditional and familial risk factors for preeclampsia in the FINNPEC cohort
CONCLUSIONS: In the FINNPEC cohort, PE women had similar socioeconomic status, more non-communicable diseases and depression, earlier menarche, more subfertility and more parental non-communicable diseases compared to controls. As a novel finding we found more mental disorders including depression in mothers of PE women. -
An expanded analysis framework for multivariate GWAS connects inflammatory biomarkers to functional variants and disease
Multivariate methods are known to increase the statistical power to detect associations in the case of shared genetic basis between phenotypes. They have, however, lacked essential analytic tools to follow-up and understand the biology underlying these associations. We developed a novel computational workflow for multivariate GWAS follow-up analyses, including fine-mapping and identification of the subset of traits driving associations (driver traits). Many follow-up tools require univariate... -
Maternal antenatal stress and mental and behavioral disorders in their children
CONCLUSION: Maternal antenatal stress is associated with higher risk of childhood mental and behavioral disorders. Efforts to reduce maternal antenatal stress should be given a high priority to improve child mental health.
2020
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Association and risk prediction of 19 complex diseases with polygenic scores and socioeconomic status
CONCLUSIONS: Genetic variation and social circumstances are linked to differences in disease risk both independently, and in combination with one another. Considering both factors modestly improves identification of higher-risk groups and highlights the value of accounting for social context alongside inherited variation in population-level assessments. -
Monoallelic TYROBP deletion is a novel risk factor for Alzheimer's disease
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population... -
Narcolepsy as a potential risk factor for Schizophrenia
Narcolepsy is a severe sleep disorder with characteristics of fatigue, fragmented sleep, cataplexy and hypnagogic hallucinations. Earlier clinical studies have reported the onset of schizophrenia after narcolepsy but the causality behind narcolepsy and schizophrenia is unknown. Our goal was to understand the causality between narcolepsy and schizophrenia. To estimate the comorbidity between narcolepsy and schizophrenia, we employed data from the FinRegistry that contains data for the total... -
Risk assessment of hypertensive disorders of pregnancy and other adverse pregnancy outcomes after frozen embryo transfers following an artificial cycle: A retrospective cohort study
CONCLUSION: The risk of HDP and several other maternal complications seems to be increased after AC-FET compared with CL-FET. Our findings support most earlier studies regarding HDP and add to the knowledge on other maternal and perinatal risks involved in AC-FET, including an increased risk of milder forms of placental retention. More studies are needed to confirm these findings. -
Patterns of reproductive health in inflammatory rheumatic diseases and other immune-mediated diseases: a nationwide registry study
CONCLUSION: Rheumatic diseases have a broad impact on reproductive health, with effects comparable with that of several other IMDs. Of the rheumatic diseases, SLE and SS conferred the largest risk increases on perinatal adverse event outcomes. -
Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy
CONCLUSIONS AND RELEVANCE: The findings indicate that genes related to blood pressure traits are associated with preeclampsia, but many of these genes have additional pleiotropic effects on cardiometabolic, endothelial, and placental function. Furthermore, several of the associated loci have no known connection with cardiovascular disease but instead harbor genes contributing to maintenance of successful pregnancy, with dysfunctions leading to preeclampsialike symptoms. -
Leveraging Northern European population history: novel low-frequency variants for polycystic ovary syndrome
STUDY QUESTION: Can we identify novel variants associated with polycystic ovary syndrome (PCOS) by leveraging the unique population history of Northern Europe? -
Association of the MYOC p.(Gln368Ter) Variant With Glaucoma in a Finnish Population
CONCLUSIONS AND RELEVANCE: This genetic association study found that the MYOC p.(Gln368Ter) variant was associated with exfoliation glaucoma. The association with normal-tension glaucoma could not be replicated. These findings suggest that MYOC p.(Gln368Ter) was associated with open-angle glaucoma and exfoliation glaucoma in a Finnish population. -
A systematic review and meta-analysis on the association between ICSI and chromosome abnormalities
BACKGROUND: In the decade following the introduction of ICSI, a higher prevalence of de novo chromosome abnormalities, in particular sex chromosome and autosomal structural abnormalities, as well as inherited abnormalities was described in children conceived by ICSI compared to both naturally conceived (NC) children and children conceived by standard IVF. The explanation for the observed increase in prevalence is not clear and has been suggested to reflect parental factors (e.g. age or sperm... -
A polyepigenetic glucocorticoid exposure score at birth and childhood mental and behavioral disorders
CONCLUSIONS: These findings suggest that fetal polyepigenetic GC exposure score at birth was not associated with any mental or behavioral disorder diagnosis or mother-rated total behavior problems, but it may contribute to identifying children at birth who are at risk for more severe mental or behavioral disorders. -
Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis
CONCLUSION: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. -
The role of polygenic risk and susceptibility genes in breast cancer over the course of life
Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their utility in various clinical situations. Here we show that among 122,978 women in the FinnGen study with 8401 breast cancer cases, the PRS modifies the breast cancer risk of two high-impact frameshift risk variants. Similarly, we show that after the breast cancer diagnosis, individuals with elevated PRS have an elevated risk of developing contralateral breast cancer,... -
Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women
Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at... -
The non-traditional and familial risk factors for preeclampsia in the FINNPEC cohort
CONCLUSIONS: In the FINNPEC cohort, PE women had similar socioeconomic status, more non-communicable diseases and depression, earlier menarche, more subfertility and more parental non-communicable diseases compared to controls. As a novel finding we found more mental disorders including depression in mothers of PE women. -
Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis
Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of... -
External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis
CONCLUSIONS: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across... -
An expanded analysis framework for multivariate GWAS connects inflammatory biomarkers to functional variants and disease
Multivariate methods are known to increase the statistical power to detect associations in the case of shared genetic basis between phenotypes. They have, however, lacked essential analytic tools to follow-up and understand the biology underlying these associations. We developed a novel computational workflow for multivariate GWAS follow-up analyses, including fine-mapping and identification of the subset of traits driving associations (driver traits). Many follow-up tools require univariate... -
Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells
Myeloproliferative neoplasms (MPNs) are blood cancers that are characterized by the excessive production of mature myeloid cells and arise from the acquisition of somatic driver mutations in haematopoietic stem cells (HSCs). Epidemiological studies indicate a substantial heritable component of MPNs that is among the highest known for cancers¹. However, only a limited number of genetic risk loci have been identified, and the underlying biological mechanisms that lead to the acquisition of MPNs... -
Maternal antenatal stress and mental and behavioral disorders in their children
CONCLUSION: Maternal antenatal stress is associated with higher risk of childhood mental and behavioral disorders. Efforts to reduce maternal antenatal stress should be given a high priority to improve child mental health. -
Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia
BACKGROUND: Fetal immune tolerance is crucial for pregnancy success. We studied the link between preeclampsia, a severe pregnancy disorder with uncertain pathogenesis, and fetal human leukocyte antigen G (HLA-G) and other genes regulating maternal immune responses. -
Therapeutic doses of metformin do not have impact on angiogenesis in presence of sera from pre-eclamptic, IUGR and healthy pregnancies
Recent evidence suggests that metformin may prevent pre-eclampsia by reverting the angiogenic imbalance in maternal sera. In this study, we investigated effect of metformin on angiogenesis by quantifying tubule formation in a human-based in vitro test with co-culture of human adipose stromal cell (hASC) and human umbilical vein endothelial cell (HUVEC). A total of 20 pregnant women were recruited in the study. Serum samples were obtained from women with early- and late-onset pre-eclampsia and... -
Polygenic prediction of the risk of perinatal depressive symptoms
CONCLUSIONS: Polygenic risk scores for major depressive disorder, schizophrenia, and cross-disorder in non-perinatal populations generalize to perinatal depressive symptoms and may afford to identify women for timely preventive interventions. -
Predisposition to superimposed preeclampsia in women with chronic hypertension: endothelial, renal, cardiac, and placental factors in a prospective longitudinal cohort
CONCLUSION: Decreased syndecan-1 and PlGF concentrations implicate endothelial glycocalyx disturbance and reduced placental angiogenic capacity, respectively, in the pathophysiology of superimposed preeclampsia. -
Cohort Profile: The Finnish Gestational Diabetes (FinnGeDi) Study
No abstract -
Maternal Hypertensive Pregnancy Disorders and Mental Disorders in Children
The associations of maternal hypertensive pregnancy disorders with offspring mental disorders remain unclear. We examined whether maternal hypertensive disorders and maximum blood pressure during pregnancy predict offspring childhood mental disorders, whether the associations are independent of maternal and paternal mental disorders and paternal hypertensive disorders, independent of or additive with maternal early pregnancy overweight/obesity and diabetes mellitus disorders, and mediated or... -
Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers
Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases^(1-3). We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease... -
Pregnancy outcomes according to the definition of gestational diabetes
CONCLUSIONS: GDM prevalence was 2.4-fold higher according to the IADPSG compared with the NICE criteria but the LGA rate did not differ. BWSDS and CS rate were increased already with mild untreated hyperglycaemia. -
Persistently High Levels of Maternal Antenatal Inflammation Are Associated With and Mediate the Effect of Prenatal Environmental Adversities on Neurodevelopmental Delay in the Offspring
CONCLUSIONS: Higher levels of maternal inflammation, especially when persisting throughout pregnancy, increase a child's risk of neurodevelopmental delay and mediate the effect of prenatal environmental adversity on child neurodevelopmental delay. -
Maternal depression and inflammation during pregnancy
CONCLUSIONS: Depression is associated with a proinflammatory state during pregnancy. These associations are mediated by early pregnancy BMI, and depressive symptoms during pregnancy aggravate the inflammation related to obesity. -
Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation
Prenatal stress exposure is associated with risk for psychiatric disorders later in life. This may be mediated in part via enhanced exposure to glucocorticoids (GCs), which are known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on messenger RNA (mRNA) expression and DNA methylation... -
Associations of antenatal glucocorticoid exposure with mental health in children
CONCLUSIONS: Antenatal betamethasone exposure may be associated with mental health problems in children born preterm and in those who end up being born at term. -
Infant regulatory behavior problems during first month of life and neurobehavioral outcomes in early childhood
Whether infant regulatory behavior problems already in the first month of life indicate an increased risk of childhood neurobehavioral problems, and whether maternal depression in the postpartum and early childhood underpins these associations remain unclear. Altogether, 2049-2364 mothers from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Neonatal Perception Inventory on regulatory behavior problems at the infant's age of 15.6 days...
2019
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Cohort profile update: the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC)
PURPOSE: The Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) study was originally established between 2008 and 2011 to develop a nationwide clinical and genomic database. By enrolling women with and without pre-eclampsia (PE), alongside their partners and infants, the study aims to identify the genetic and molecular determinants of PE. This update summarises the final dataset, reviews key findings since the 2016 cohort profile, and outlines current research directions. -
Monoallelic TYROBP deletion is a novel risk factor for Alzheimer's disease
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population... -
External causes are leading causes of death in women of reproductive age: a registry study on maternal perinatal health, hypertensive pregnancy disorders and mortality in Finland
CONCLUSIONS: Reproductive history, specifically preventable and CVD cause, has a significant role in mortality of women of reproductive age. Women have an increased risk of CVD death, and reduced survival of CVD mortality, if they have PE or other HDP, in the pregnancy associated with their first birth. -
Narcolepsy as a potential risk factor for Schizophrenia
Narcolepsy is a severe sleep disorder with characteristics of fatigue, fragmented sleep, cataplexy and hypnagogic hallucinations. Earlier clinical studies have reported the onset of schizophrenia after narcolepsy but the causality behind narcolepsy and schizophrenia is unknown. Our goal was to understand the causality between narcolepsy and schizophrenia. To estimate the comorbidity between narcolepsy and schizophrenia, we employed data from the FinRegistry that contains data for the total... -
Metabolic profiles of meconium in preeclamptic and normotensive pregnancies
CONCLUSION: PE is associated with alterations in the meconium metabolome of infants. The differing abundances of several metabolites show alterations in the interaction between the fetoplacental unit and mother in PE, but whether they are a cause or an effect of the disorder remains to be further investigated. -
Development and validation of a prognostic model to predict birth weight: individual participant data meta-analysis
CONCLUSIONS: The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other... -
Comprehensive Inherited Risk Estimation for Risk-Based Breast Cancer Screening in Women
CONCLUSION: Using real-life screening data, this study demonstrates the effectiveness of a breast cancer PRS for risk stratification, alone and combined with FH and PVs. Further research is required to evaluate their impact in a prospective risk-stratified screening program, including cost-effectiveness. -
Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy
CONCLUSIONS AND RELEVANCE: The findings indicate that genes related to blood pressure traits are associated with preeclampsia, but many of these genes have additional pleiotropic effects on cardiometabolic, endothelial, and placental function. Furthermore, several of the associated loci have no known connection with cardiovascular disease but instead harbor genes contributing to maintenance of successful pregnancy, with dysfunctions leading to preeclampsialike symptoms. -
New insights into the genetic etiology of Alzheimer's disease and related dementias
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted... -
Association of the MYOC p.(Gln368Ter) Variant With Glaucoma in a Finnish Population
CONCLUSIONS AND RELEVANCE: This genetic association study found that the MYOC p.(Gln368Ter) variant was associated with exfoliation glaucoma. The association with normal-tension glaucoma could not be replicated. These findings suggest that MYOC p.(Gln368Ter) was associated with open-angle glaucoma and exfoliation glaucoma in a Finnish population. -
External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis
CONCLUSIONS: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across... -
Persistently High Levels of Maternal Antenatal Inflammation Are Associated With and Mediate the Effect of Prenatal Environmental Adversities on Neurodevelopmental Delay in the Offspring
CONCLUSIONS: Higher levels of maternal inflammation, especially when persisting throughout pregnancy, increase a child's risk of neurodevelopmental delay and mediate the effect of prenatal environmental adversity on child neurodevelopmental delay. -
Longitudinal changes in plasma hemopexin and alpha-1-microglobulin concentrations in women with and without clinical risk factors for pre-eclampsia
Recent studies have shown increased concentration of fetal hemoglobin (HbF) in pre-eclamptic women. Plasma hemopexin (Hpx) and alpha-1-microglobulin (A1M) are hemoglobin scavenger proteins that protect against toxic effects of free heme released in the hemoglobin degradation process. We used an enzyme-linked immunosorbent assay to analyze maternal plasma Hpx and A1M concentrations at 12-14, 18-20 and 26-28 weeks of gestation in three groups: 1) 51 women with a low risk for pre-eclampsia (LRW),... -
Author Correction: Exome sequencing of Finnish isolates enhances rare-variant association power
An Amendment to this paper has been published and can be accessed via a link at the top of the paper. -
Genetic architecture of human plasma lipidome and its link to cardiovascular disease
Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10^(-8)), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and... -
Maternal depression and inflammation during pregnancy
CONCLUSIONS: Depression is associated with a proinflammatory state during pregnancy. These associations are mediated by early pregnancy BMI, and depressive symptoms during pregnancy aggravate the inflammation related to obesity. -
Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation
Prenatal stress exposure is associated with risk for psychiatric disorders later in life. This may be mediated in part via enhanced exposure to glucocorticoids (GCs), which are known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on messenger RNA (mRNA) expression and DNA methylation... -
Exome sequencing of Finnish isolates enhances rare-variant association power
Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of... -
Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns
Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219... -
Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns
Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts... -
Pregnancy-associated stroke -a systematic review of subsequent pregnancies and maternal health
CONCLUSIONS: Data on subsequent pregnancies and health of women with a history of pregnancy-associated stroke are limited. Further research on this topic is essential for adequate counselling and secondary prevention. -
Plasma Heme Scavengers Alpha-1-Microglobulin and Hemopexin as Biomarkers in High-Risk Pregnancies
Women with established preeclampsia (PE) have increased plasma concentration of free fetal hemoglobin. We measured two hemoglobin scavenger system proteins, hemopexin (Hpx) and alpha-1-microglobulin (A1M) in maternal plasma using enzyme-linked immunosorbent assay during the late second trimester of pregnancy in women with high and low risk of developing PE. In total 142 women were included in nested case-control study: 42 women diagnosed with PE and 100 controls (49 randomly selected high-risk... -
Temporal and external validation of the fullPIERS model for the prediction of adverse maternal outcomes in women with pre-eclampsia
The fullPIERS model is a risk prediction model developed to predict adverse maternal outcomes within 48 h for women admitted with pre-eclampsia. External validation of the model is required before implementation for clinical use. We assessed the temporal and external validity of the fullPIERS model in high income settings using five cohorts collected between 2003 and 2016, from tertiary hospitals in Canada, the United States of America, Finland and the United Kingdom. The cohorts were grouped... -
Maternal depressive symptoms during and after pregnancy are associated with poorer sleep quantity and quality and sleep disorders in 3.5-year-old offspring
CONCLUSION: Maternal depressive symptoms throughout pregnancy are associated with mother-rated child sleep quantity, quality, and disorders. Maternal depressive symptoms at child follow-up mediate and add to the prenatal adverse effects on child sleep characteristics. -
The health of children conceived by ART: 'the chicken or the egg?'
Worldwide, more than 7 million children have now been born after ART: these delivery rates are steadily rising and now comprise 2-6% of births in the European countries. To achieve higher pregnancy rates, the transfer of two or more embryos was previously the gold standard in ART. However, recently the practise has moved towards a single embryo transfer policy to avoid multiple births. The positive consequences of the declining multiple birth rates after ART are decreasing perinatal risks and... -
Associations of antenatal glucocorticoid exposure with mental health in children
CONCLUSIONS: Antenatal betamethasone exposure may be associated with mental health problems in children born preterm and in those who end up being born at term. -
Infant regulatory behavior problems during first month of life and neurobehavioral outcomes in early childhood
Whether infant regulatory behavior problems already in the first month of life indicate an increased risk of childhood neurobehavioral problems, and whether maternal depression in the postpartum and early childhood underpins these associations remain unclear. Altogether, 2049-2364 mothers from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Neonatal Perception Inventory on regulatory behavior problems at the infant's age of 15.6 days... -
Impact of obesity on angiogenic and inflammatory markers in the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort
CONCLUSIONS: We confirmed increased pre-pregnancy BMI in women with PE. Enhanced inflammatory state was confirmed in all women with overweight/obesity. Partly paradoxically we observed that PE women with obesity had less disturbed levels of angiogenic markers than normal weight women with PE. This should be taken into account when angiogenic markers are used in PE prediction.
2018
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Early abduction treatment versus observation in Barlow-positive and mildly unstable hips
CONCLUSION: Observation for about a month in clinically mildly unstable hips with or without Barlow positive signs seems safe regarding the recovery of alpha angles, treatment duration and treatment failures. More research is needed for longer observation times. -
Monoallelic TYROBP deletion is a novel risk factor for Alzheimer's disease
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population... -
Narcolepsy as a potential risk factor for Schizophrenia
Narcolepsy is a severe sleep disorder with characteristics of fatigue, fragmented sleep, cataplexy and hypnagogic hallucinations. Earlier clinical studies have reported the onset of schizophrenia after narcolepsy but the causality behind narcolepsy and schizophrenia is unknown. Our goal was to understand the causality between narcolepsy and schizophrenia. To estimate the comorbidity between narcolepsy and schizophrenia, we employed data from the FinRegistry that contains data for the total... -
Development and validation of a prognostic model to predict birth weight: individual participant data meta-analysis
CONCLUSIONS: The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other... -
Costs of abduction treatment in developmental dysplasia of the hip. Analysis of 900 patients
CONCLUSION: With correct patient selection, a watchful waiting strategy is cost-effective in treating mild developmental dysplasia of the hip, considering the high percentage of spontaneous recovery. -
Known risk factors of the developmental dysplasia of the hip predicting more severe clinical presentation and failure of Pavlik harness treatment
CONCLUSION: Breech presentation seems to increase the risk of Ortolani positive DDH. However, these infants are likely to recover with initially started Pavlik harness treatment, as it was not associated with elevated risk for undergoing more robust treatments. Positive family history and girl sex are associated with the most severe cases of developmental dysplasia of the hip, and it may predispose to the failure of the Pavlik harness treatment. -
Clinical and sonographic improvement of developmental dysplasia of the hip: analysis of 948 patients
CONCLUSION: Female sex and positive family history might be independent risk factors for slower recovery in DDH before 6 months of age. These children might need special attention in their follow-up plans and abduction treatment. -
Maternal exposure to childhood maltreatment and mental and behavioral disorders in children
Exposure to maltreatment in childhood is associated with lifelong risk of mental and behavioral disorders. Whether the effects extend to the next generation remains unclear. We examined whether maternal exposure to childhood abuse and neglect in her own childhood were associated with mental and behavioral disorders and psychiatric symptoms in her children, and whether maternal lifetime mental and behavioral disorders or lower education level mediated or added to the effects. Mothers (n = 2252)... -
Obstetric early warning system to predict maternal morbidity of pre-eclampsia, postpartum hemorrhage and infection after birth in high-risk women: a prospective cohort study
OBJECTIVE: The purpose of early warning systems is to detect deterioration of the patient and to enable timely intervention to prevent possible severe illness. The most common causes of maternal morbidity and mortality after birth are worsening pre-eclampsia, postpartum haemorrhage and puerperal infection. Our aim was to validate the accuracy of the obstetric early warning system and different physiological triggers to predict morbidity on the postnatal ward in high-risk women. -
Routine Bedside Use of Obstetric Early Warning System in the Postnatal Ward to Identify Maternal Morbidity Among High-Risk Women
CONCLUSIONS: In high-risk women, OEWS revealed one-half of the morbidity. Women with PPH and preeclampsia benefited most from it. Abnormal blood pressure and pulse had the strongest associations with morbidity. -
Pregnancy-associated stroke -a systematic review of subsequent pregnancies and maternal health
CONCLUSIONS: Data on subsequent pregnancies and health of women with a history of pregnancy-associated stroke are limited. Further research on this topic is essential for adequate counselling and secondary prevention. -
Temporal and external validation of the fullPIERS model for the prediction of adverse maternal outcomes in women with pre-eclampsia
The fullPIERS model is a risk prediction model developed to predict adverse maternal outcomes within 48 h for women admitted with pre-eclampsia. External validation of the model is required before implementation for clinical use. We assessed the temporal and external validity of the fullPIERS model in high income settings using five cohorts collected between 2003 and 2016, from tertiary hospitals in Canada, the United States of America, Finland and the United Kingdom. The cohorts were grouped... -
Maternal depressive symptoms during and after pregnancy are associated with poorer sleep quantity and quality and sleep disorders in 3.5-year-old offspring
CONCLUSION: Maternal depressive symptoms throughout pregnancy are associated with mother-rated child sleep quantity, quality, and disorders. Maternal depressive symptoms at child follow-up mediate and add to the prenatal adverse effects on child sleep characteristics. -
The Immunogenetic Conundrum of Preeclampsia
Pregnancy is an immunological challenge to the mother. The fetal tissues including the placenta must be protected from activation of the maternal immune system. On the other hand, the placental tissue sheds into the maternal circulation and must be adequately identified and phagocytized by the maternal immune system. During a healthy pregnancy, numerous immunosuppressive processes take place that allow the allograft fetus to thrive under exposure to humoral and cellular components of the... -
Infant regulatory behavior problems during first month of life and neurobehavioral outcomes in early childhood
Whether infant regulatory behavior problems already in the first month of life indicate an increased risk of childhood neurobehavioral problems, and whether maternal depression in the postpartum and early childhood underpins these associations remain unclear. Altogether, 2049-2364 mothers from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Neonatal Perception Inventory on regulatory behavior problems at the infant's age of 15.6 days... -
Neonatal regulatory behavior problems are predicted by maternal early pregnancy overweight and obesity: findings from the prospective PREDO Study
CONCLUSION: Regulatory behavior problems of the offspring have prenatal origins and partially mediate the effects of maternal overweight/obesity on offspring neurodevelopment. -
A Non-Targeted LC-MS Profiling Reveals Elevated Levels of Carnitine Precursors and Trimethylated Compounds in the Cord Plasma of Pre-Eclamptic Infants
Preeclampsia (PE) is a complex pregnancy disorder. It is not extensively known how the metabolic alterations of PE women contribute to the metabolism of newborn. We applied liquid chromatography-mass spectrometry (LC-MS) based non-targeted metabolomics to determine whether the metabolic profile of plasma from umbilical cord differs between infants born to PE and non-PE pregnancies in the FINNPEC study. Cord plasma was available from 42 newborns born from PE and 53 from non-PE pregnancies. 133... -
Impact of obesity on angiogenic and inflammatory markers in the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort
CONCLUSIONS: We confirmed increased pre-pregnancy BMI in women with PE. Enhanced inflammatory state was confirmed in all women with overweight/obesity. Partly paradoxically we observed that PE women with obesity had less disturbed levels of angiogenic markers than normal weight women with PE. This should be taken into account when angiogenic markers are used in PE prediction. -
Prevention of gestational diabetes with a prepregnancy lifestyle intervention - findings from a randomized controlled trial
CONCLUSION: The preconceptional lifestyle intervention applied in the present study did not reduce the incidence of GDM. -
Effect of a lifestyle intervention during pregnancy-findings from the Finnish gestational diabetes prevention trial (RADIEL)
CONCLUSIONS: The high prevalence of impaired glucose metabolism was observed already in early pregnancy, which may have contributed to the lack of effect of the intervention. -
Prediction of pre-eclampsia and its subtypes in high-risk cohort: hyperglycosylated human chorionic gonadotropin in multivariate models
CONCLUSIONS: Although the multivariate models did not meet the requirements to be clinically useful screening tools, our results indicate that the biomarker profile in women with risk factors for PE is different according to the subtype of PE. The heterogeneous nature of PE results in difficulty to find new, clinically useful biomarkers for prediction of PE in early pregnancy in high-risk cohorts. -
Polycystic ovary syndrome and risk factors for gestational diabetes
CONCLUSIONS: The increased risk of GDM in women with PCOS was related to obesity and increased maternal age rather than to PCOS itself, suggesting that routine early screening of GDM in PCOS women without other risk factors should be reconsidered. Instead, family history of GDM/T2D and own preterm birth were independent risk factors for GDM. -
Angiogenic profile in the Finnish Genetics of Pre-Eclampsia Consortium (FINNPEC) cohort
CONCLUSIONS: Primiparous pregnancies have more anti-angiogenic profile during second/third trimester compared with multiparous pregnancies. Our findings also suggest that certain maternal characteristics, e.g. BMI, smoking and pre-existing diseases, should be taken into account when different sFlt-1/PlGF ratio cut-offs are utilized. -
The Epigenetic Clock at Birth: Associations With Maternal Antenatal Depression and Child Psychiatric Problems
CONCLUSION: Maternal antenatal depression is associated with lower epigenetic GA in offspring. This lower epigenetic GA seems to be associated with a developmental disadvantage for boys, who, in early childhood, show greater psychiatric problems. -
Maternal early pregnancy obesity and related pregnancy and pre-pregnancy disorders: associations with child developmental milestones in the prospective PREDO Study
CONCLUSIONS: Maternal early pregnancy overweight, obesity, and pre-eclampsia are independently associated with neurodevelopmental delay in her offspring. Further studies unraveling the underlying mechanisms are warranted. -
Maternal depressive symptoms during and after pregnancy and child developmental milestones
CONCLUSION: Maternal depressive symptoms during pregnancy, in the first year postpartum and in early childhood are associated with poorer child neurodevelopment. Our findings further suggest that antenatal and postpregnancy depression have additive effects on neurodevelopment. Children of mothers with the most chronic and severe depressive symptoms during pregnancy had the most neurodevelopmental disadvantages. Our findings emphasize the adverse effects of maternal depression during and after... -
The effect of paternal factors on perinatal and paediatric outcomes: a systematic review and meta-analysis
BACKGROUND: Maternal factors, including increasing childbearing age and various life-style factors, are associated with poorer short- and long-term outcomes for children, whereas knowledge of paternal parameters is limited. Recently, increasing paternal age has been associated with adverse obstetric outcomes, birth defects, autism spectrum disorders and schizophrenia in children. -
Maternal early pregnancy obesity and depressive symptoms during and after pregnancy
CONCLUSIONS: Maternal early pregnancy overweight and obesity and depressive symptoms during and after pregnancy are associated. Mental health promotion should be included as an integral part of lifestyle interventions in early pregnancy obesity and extended to benefit also overweight and underweight women. -
Placental Morphology Is Associated with Maternal Depressive Symptoms during Pregnancy and Toddler Psychiatric Problems
Maternal depressive symptoms during pregnancy predict increased psychiatric problems in children. The underlying biological mechanisms remain unclear. Hence, we examined whether alterations in the morphology of 88 term placentas were associated with maternal depressive symptoms during pregnancy and psychiatric problems in 1.9-3.1-years old (Mean = 2.1 years) toddlers. Maternal depressive symptoms were rated biweekly during pregnancy with the Center of Epidemiological Studies Depression Scale (n... -
Identification of OAF and PVRL1 as candidate genes for an ocular anomaly characterized by Peters anomaly type 2 and ectopia lentis
Keratolenticular dysgenesis (KLD) and ectopia lentis are congenital eye defects. The aim of this study is the identification of molecular genetic alterations responsible for those ocular anomalies with neurologic impairment in an individual with a de novo balanced chromosome translocation t(11;18)(q23.3;q11.2)dn. Disruption of OAF, the human orthologue of the Drosophila oaf, by the 11q23.3 breakpoint results in reduced expression of this transcriptional regulator. Furthermore, four most likely... -
Fetal Microsatellite in the Heme Oxygenase 1 Promoter Is Associated With Severe and Early-Onset Preeclampsia
Preeclampsia is a vascular pregnancy disorder that often involves impaired placental development. HO-1 (heme oxygenase 1, encoded by HMOX1) is a stress response enzyme crucial for endothelial and placental function. Long version of the guanine-thymine (GT(n)) microsatellite in the HMOX1 promoter decreases HO-1 expression, and the long maternal repeat is associated with late-onset preeclampsia. Our aim was to study whether the length of fetal repeat is associated with mother's preeclampsia,...
2017
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Monoallelic TYROBP deletion is a novel risk factor for Alzheimer's disease
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer's disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population... -
Narcolepsy as a potential risk factor for Schizophrenia
Narcolepsy is a severe sleep disorder with characteristics of fatigue, fragmented sleep, cataplexy and hypnagogic hallucinations. Earlier clinical studies have reported the onset of schizophrenia after narcolepsy but the causality behind narcolepsy and schizophrenia is unknown. Our goal was to understand the causality between narcolepsy and schizophrenia. To estimate the comorbidity between narcolepsy and schizophrenia, we employed data from the FinRegistry that contains data for the total... -
Development and validation of a prognostic model to predict birth weight: individual participant data meta-analysis
CONCLUSIONS: The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other... -
Birth injury in breech delivery: a nationwide population-based cohort study in Finland
CONCLUSION: Birth injuries were rare in vaginal breech deliveries. The incidence of severe birth injury was two times higher in vaginal breech delivery compared to cephalic vaginal delivery. Brachial plexus palsy was the most common type of injury in vaginal breech delivery. -
Incidence changes in risk factors associated with the decreasing number of birth-related clavicle fractures in Finland: A nationwide retrospective birth cohort from 2004 to 2017
BACKGROUND: A clavicle fracture is one of the most common birth injuries. The objective of this study was to examine whether the decreased incidence of birth-related clavicle fractures in Finland is because of temporal changes in their predisposing factors. -
Cohort profile: InTraUterine sampling in early pregnancy (ITU), a prospective pregnancy cohort study in Finland: study design and baseline characteristics
PURPOSE: The InTraUterine sampling in early pregnancy (ITU) is a prospective pregnancy cohort study. The overarching aim of ITU is to unravel genomic, epigenomic, transcriptomic, endocrine, inflammatory and metabolic maternal-placental-fetal mechanisms involved in the programming of health and disease after exposure to prenatal environmental adversity, such as maternal malnutrition, cardiometabolic disorders, infections, medical interventions, mental disorders and psychosocial stress. This paper... -
Severe birth injuries in neonates and associated risk factors for injury in mothers with different types of diabetes in Finland
CONCLUSION: Neonates of women with pregestational diabetes have a higher risk for severe birth injury than other neonates. The injury risk in neonates delivered by women with gestational diabetes or non-diabetic women is generally low. -
Association of the MYOC p.(Gln368Ter) Variant With Glaucoma in a Finnish Population
CONCLUSIONS AND RELEVANCE: This genetic association study found that the MYOC p.(Gln368Ter) variant was associated with exfoliation glaucoma. The association with normal-tension glaucoma could not be replicated. These findings suggest that MYOC p.(Gln368Ter) was associated with open-angle glaucoma and exfoliation glaucoma in a Finnish population. -
The effect of paternal factors on perinatal and paediatric outcomes: a systematic review and meta-analysis
BACKGROUND: Maternal factors, including increasing childbearing age and various life-style factors, are associated with poorer short- and long-term outcomes for children, whereas knowledge of paternal parameters is limited. Recently, increasing paternal age has been associated with adverse obstetric outcomes, birth defects, autism spectrum disorders and schizophrenia in children. -
Maternal depressive symptoms during and after pregnancy are associated with attention-deficit/hyperactivity disorder symptoms in their 3- to 6-year-old children
Maternal depressive symptoms during pregnancy have been associated with child behavioural symptoms of attention-deficit/hyperactivity disorder (ADHD) in early childhood. However, it remains unclear if depressive symptoms throughout pregnancy are more harmful to the child than depressive symptoms only during certain times, and if maternal depressive symptoms after pregnancy add to or mediate any prenatal effects. 1,779 mother-child dyads participated in the Prediction and Prevention of... -
Fetal Microsatellite in the Heme Oxygenase 1 Promoter Is Associated With Severe and Early-Onset Preeclampsia
Preeclampsia is a vascular pregnancy disorder that often involves impaired placental development. HO-1 (heme oxygenase 1, encoded by HMOX1) is a stress response enzyme crucial for endothelial and placental function. Long version of the guanine-thymine (GT(n)) microsatellite in the HMOX1 promoter decreases HO-1 expression, and the long maternal repeat is associated with late-onset preeclampsia. Our aim was to study whether the length of fetal repeat is associated with mother's preeclampsia,... -
Protective Low-Frequency Variants for Preeclampsia in the Fms Related Tyrosine Kinase 1 Gene in the Finnish Population
Preeclampsia is a common pregnancy-specific vascular disorder characterized by new-onset hypertension and proteinuria during the second half of pregnancy. Predisposition to preeclampsia is in part heritable. It is associated with an increased risk of cardiovascular disease later in life. We have sequenced 124 candidate genes implicated in preeclampsia to pinpoint genetic variants contributing to predisposition to or protection from preeclampsia. First, targeted exomic sequencing was performed in... -
Variants in the fetal genome near FLT1 are associated with risk of preeclampsia
Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility... -
Erratum. Gestational Diabetes Mellitus Can Be Prevented by Lifestyle Intervention: The Finnish Gestational Diabetes Prevention Study (RADIEL). A Randomized Controlled Trial. Diabetes Care 2016;39:24-30
No abstract -
Analysis of Complement <em>C3</em> Gene Reveals Susceptibility to Severe Preeclampsia
Preeclampsia (PE) is a common vascular disease of pregnancy with genetic predisposition. Dysregulation of the complement system has been implicated, but molecular mechanisms are incompletely understood. In this study, we determined the potential linkage of severe PE to the most central complement gene, C3. Three cohorts of Finnish patients and controls were recruited for a genetic case-control study. Participants were genotyped using Sequenom genotyping and Sanger sequencing. Initially, we... -
Angiogenic profile and smoking in the Finnish Genetics of Pre-Eclampsia Consortium (FINNPEC) cohort
CONCLUSIONS: The protective effect of smoking in reducing the risk of PE may be due to the early pregnancy change towards pro-angiogenic marker profile. Also, in late pregnancy, smoking exerted effect in sFlt-1/PlGF ratio in PE pregnancies, and may complicate its use as a prognostic and diagnostic marker. Key messages Smoking appears to have angiogenic effects in early pregnancy with reduced sEng concentrations and elevated PlGF concentrations in both normal and PE pregnancies. Throughout... -
Associations between maternal risk factors of adverse pregnancy and birth outcomes and the offspring epigenetic clock of gestational age at birth
CONCLUSIONS: Our findings show that variations in the DNAm GA of the offspring at birth are associated with a number of maternal and offspring characteristics known to reflect exposure to prenatal environmental adversity. Future studies should be aimed at determining if this biological variation is predictive of developmental adversity. -
SIRT6 polymorphism rs117385980 is associated with longevity and healthy aging in Finnish men
CONCLUSIONS: These results suggest an inverse association between the T allele of rs117385980 and longevity. The result needs to be confirmed in a larger study. It remains to be determined whether rs117385980 itself has an effect or if it is a mere genetic marker for some other yet undiscovered sequence variant causing a functional effect. -
Cluster analysis to estimate the risk of preeclampsia in the high-risk Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study
CONCLUSION: The risk of preeclampsia increases exponentially with respect to the number of risk factors. Early-onset preeclampsia and severe preeclampsia have different risk profile from term preeclampsia. -
Maternal Depressive Symptoms During and After Pregnancy and Psychiatric Problems in Children
CONCLUSION: Maternal depressive symptoms during pregnancy predict increased psychiatric problems in young children. Preventive interventions from early pregnancy onward may benefit offspring mental health. -
Cohort Profile: Prediction and prevention of preeclampsia and intrauterine growth restriction (PREDO) study
No abstract -
Fetal sex-specific differences in gestational age at delivery in pre-eclampsia: a meta-analysis
CONCLUSIONS: Sexual dimorphic differences in the occurrence of PE exist, with preterm PE being more prevalent among pregnancies with a female fetus as compared with pregnancies with a male fetus and with no differences with respect to term PE.
2016
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Cohort profile update: the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC)
PURPOSE: The Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) study was originally established between 2008 and 2011 to develop a nationwide clinical and genomic database. By enrolling women with and without pre-eclampsia (PE), alongside their partners and infants, the study aims to identify the genetic and molecular determinants of PE. This update summarises the final dataset, reviews key findings since the 2016 cohort profile, and outlines current research directions. -
Maternal and fetal treatment outcomes of pregnancy-related aneurysmal subarachnoid hemorrhage: a nationwide study
CONCLUSIONS: Aneurysmal SAH during pregnancy is associated with exceptionally low maternal and neonatal mortality. All maternal and fetal fatalities were due to sudden prehospital deaths. Pregnancy-related immunological modulation and its potential benefits on aSAH outcomes represent a compelling topic for future research. -
A Population-Based Study of Posterior Reversible Encephalopathy Syndrome and Reversible Cerebral Vasoconstriction Syndrome During Pregnancy and Puerperium
CONCLUSIONS: Pregnancy-associated PRES and RCVS are potentially life-threatening, rare conditions that can result in hemorrhagic stroke. PRES ± RCVS is strongly associated with preeclampsia with severe features, whereas puerperal RCVS seems to be a separate, later-occurring condition. -
Long-Term Recovery, Morbidity, and Mortality After Maternal Ischemic Stroke
BACKGROUND AND OBJECTIVES: The long-term prognosis after maternal ischemic stroke (IS) remains understudied. The objectives were to examine if mortality and long-term morbidity are more frequent in women with prior maternal IS compared with women without a pregnancy-related stroke and to assess recovery in maternal IS patients based on functional outcomes and vocational status. -
Stroke Recurrence and Pregnancy Outcomes in the Subsequent Pregnancies After Maternal Ischemic Stroke
CONCLUSIONS: Although most pregnancies proceed without complications, the subsequent pregnancies of women with a prior maternal IS are high-risk pregnancies that require careful planning and surveillance. They are frequently complicated with diabetes and hypertensive disorders of pregnancy, and the recurrence of IS or transient ischemic attack is notable. -
Genetic Loci Associated With Periodontitis: The FinnGen Study Based on National Health Registers
CONCLUSIONS: Our GWAS suggests that genetic variation contributing to immune dysregulation is involved in the pathogenesis of periodontitis, which has considerable genetic similarity with other complex traits. -
Intracranial Arteriovenous Malformations During Pregnancy and Puerperium-A Retrospective Nationwide Population-Based Cohort Study
CONCLUSION: Most mothers in the study had prior pregnancies, suggesting a potentially weaker association between AVM rupture and pregnancy compared to previous reports. Notably, 2 AVM ruptures occurred during spontaneous vaginal deliveries. Outcomes were generally favorable in both mothers and infants. More research is needed to refine our understanding of the optimal timing for invasive treatment during pregnancy. -
Long-Term Mortality, Recovery, and Vocational Status After a Maternal Stroke: Register-Based Observational Case-Control Study
BACKGROUND AND OBJECTIVES: Maternal stroke is a rare event with an increasing incidence. Data on the long-term prognosis after a maternal stroke are limited. We aimed to examine long-term mortality, recovery, vocational status and morbidity after a maternal stroke in a population-based setting including a comparison with matched, stroke-free controls. -
Acute recanalization therapy for ischemic stroke during pregnancy and puerperium
CONCLUSIONS: In this small nationwide cohort of maternal ISs, the complications of recanalization therapy were rare, and the outcomes were similar in IVT-treated maternal IS patients and controls. Maternal ISs should not be excluded from recanalization therapy in otherwise eligible situations. -
NTHL1 is a recessive cancer susceptibility gene
In search of novel breast cancer (BC) risk variants, we performed a whole-exome sequencing and variant analysis of 69 Finnish BC patients as well as analysed loss-of-function variants identified in DNA repair genes in the Finns from the Genome Aggregation Database. Additionally, we carried out a validation study of SERPINA3 c.918-1G>C, recently suggested for BC predisposition. We estimated the frequencies of 41 rare candidate variants in 38 genes by genotyping them in 2482-4101 BC patients and... -
Etiology of intracerebral hemorrhage during pregnancy or puerperium: A nationwide study
CONCLUSIONS: Even in a country with a comprehensive pregnancy surveillance system, the maternal mortality rate for pICH is high, and the sequelae are severe. Early recognition and treatment of the key risk factor, HDP, is crucial to help prevent this serious pregnancy complication. -
Etiology and risk factors of ischemic stroke during pregnancy and puerperium: A population-based study
INTRODUCTION: Ischemic stroke (IS) is an uncommon, but potentially life-changing, complication of pregnancy. The aim of this study was to analyze the etiology and risk factors of pregnancy-associated IS. -
Pregnancy-associated stroke and the recurrence of stroke and other complications in subsequent pregnancies: Population-based retrospective cohort study
CONCLUSIONS: Subsequent pregnancies of women with a history of PAS are more often complicated with hypertensive disorders of pregnancy and any diabetes during pregnancy. PAS recurrence risk is considerable. -
Subarachnoid Hemorrhage During Pregnancy and Puerperium: A Population-Based Study
CONCLUSIONS: The incidence of pSAH has not changed substantially over time in Finland. The majority of pSAH cases were aneurysmal and women with aneurysm had considerable mortality and morbidity. Counseling of pregnant women about smoking cessation and monitoring of blood pressure and symptoms of pre-eclampsia are important interventions to prevent pSAH. -
Obstetric early warning system to predict maternal morbidity of pre-eclampsia, postpartum hemorrhage and infection after birth in high-risk women: a prospective cohort study
OBJECTIVE: The purpose of early warning systems is to detect deterioration of the patient and to enable timely intervention to prevent possible severe illness. The most common causes of maternal morbidity and mortality after birth are worsening pre-eclampsia, postpartum haemorrhage and puerperal infection. Our aim was to validate the accuracy of the obstetric early warning system and different physiological triggers to predict morbidity on the postnatal ward in high-risk women. -
Stroke in Pregnancy and Puerperium: Validated Incidence Trends With Risk Factor Analysis in Finland 1987-2016
CONCLUSION: PAS incidence is increasing, stressing the importance of careful pregnancy surveillance and risk factor management, particularly in older expectant mothers and extending to puerperium. -
Maternal antenatal stress and mental and behavioral disorders in their children
CONCLUSION: Maternal antenatal stress is associated with higher risk of childhood mental and behavioral disorders. Efforts to reduce maternal antenatal stress should be given a high priority to improve child mental health. -
Routine Bedside Use of Obstetric Early Warning System in the Postnatal Ward to Identify Maternal Morbidity Among High-Risk Women
CONCLUSIONS: In high-risk women, OEWS revealed one-half of the morbidity. Women with PPH and preeclampsia benefited most from it. Abnormal blood pressure and pulse had the strongest associations with morbidity. -
Polygenic prediction of the risk of perinatal depressive symptoms
CONCLUSIONS: Polygenic risk scores for major depressive disorder, schizophrenia, and cross-disorder in non-perinatal populations generalize to perinatal depressive symptoms and may afford to identify women for timely preventive interventions. -
Maternal Hypertensive Pregnancy Disorders and Mental Disorders in Children
The associations of maternal hypertensive pregnancy disorders with offspring mental disorders remain unclear. We examined whether maternal hypertensive disorders and maximum blood pressure during pregnancy predict offspring childhood mental disorders, whether the associations are independent of maternal and paternal mental disorders and paternal hypertensive disorders, independent of or additive with maternal early pregnancy overweight/obesity and diabetes mellitus disorders, and mediated or... -
Temporal and external validation of the fullPIERS model for the prediction of adverse maternal outcomes in women with pre-eclampsia
The fullPIERS model is a risk prediction model developed to predict adverse maternal outcomes within 48 h for women admitted with pre-eclampsia. External validation of the model is required before implementation for clinical use. We assessed the temporal and external validity of the fullPIERS model in high income settings using five cohorts collected between 2003 and 2016, from tertiary hospitals in Canada, the United States of America, Finland and the United Kingdom. The cohorts were grouped... -
Associations of antenatal glucocorticoid exposure with mental health in children
CONCLUSIONS: Antenatal betamethasone exposure may be associated with mental health problems in children born preterm and in those who end up being born at term. -
Infant regulatory behavior problems during first month of life and neurobehavioral outcomes in early childhood
Whether infant regulatory behavior problems already in the first month of life indicate an increased risk of childhood neurobehavioral problems, and whether maternal depression in the postpartum and early childhood underpins these associations remain unclear. Altogether, 2049-2364 mothers from the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study completed the Neonatal Perception Inventory on regulatory behavior problems at the infant's age of 15.6 days... -
Erratum. Gestational Diabetes Mellitus Can Be Prevented by Lifestyle Intervention: The Finnish Gestational Diabetes Prevention Study (RADIEL). A Randomized Controlled Trial. Diabetes Care 2016;39:24-30
No abstract -
Cohort profile: the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC)
PURPOSE: The Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) Study was established to set up a nationwide clinical and DNA database on women with and without pre-eclampsia (PE), including their partners and infants, in order to identify genetic risk factors for PE. -
Maternal Depressive Symptoms During and After Pregnancy and Psychiatric Problems in Children
CONCLUSION: Maternal depressive symptoms during pregnancy predict increased psychiatric problems in young children. Preventive interventions from early pregnancy onward may benefit offspring mental health. -
First trimester serum placental growth factor and hyperglycosylated human chorionic gonadotropin are associated with pre-eclampsia: a case control study
CONCLUSIONS: First trimester maternal serum %hCG-h tended to improve prediction of preterm and early-onset pre-eclampsia when combined with PlGF, PAPP-A and maternal risk factors. -
An epigenetic clock for gestational age at birth based on blood methylation data
CONCLUSIONS: DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances. -
Investigation of rare and low-frequency variants using high-throughput sequencing with pooled DNA samples
High-throughput sequencing using pooled DNA samples can facilitate genome-wide studies on rare and low-frequency variants in a large population. Some major questions concerning the pooling sequencing strategy are whether rare and low-frequency variants can be detected reliably, and whether estimated minor allele frequencies (MAFs) can represent the actual values obtained from individually genotyped samples. In this study, we evaluated MAF estimates using three variant detection tools with two... -
Stanniocalcin-1 Hormone in Nonpreeclamptic and Preeclamptic Pregnancy: Clinical, Life-Style, and Genetic Modulators
CONCLUSIONS: Increased STC1 hormone represents a hallmark of late-onset PE. STC1 gene variants modulate placental gene expression and maternal hormone levels. -
An RGS2 3'UTR polymorphism is associated with preeclampsia in overweight women
CONCLUSIONS: Our results suggest that RGS2 might be involved in the pathogenesis of preeclampsia particularly in overweight women and contribute to their increased risk for hypertension and other types of cardiovascular disease later in life. -
The diagnosis of pre-eclampsia using two revised classifications in the Finnish Pre-eclampsia Consortium (FINNPEC) cohort
CONCLUSIONS: Only minor changes were observed in the total number of pre-eclamptic women in the FINNPEC cohort when comparing the ACOC 2002 classification with the ACOG 2013 and ISSHP 2014 classifications. -
Exome sequencing in pooled DNA samples to identify maternal pre-eclampsia risk variants
Pre-eclampsia is a common pregnancy disorder that is a major cause for maternal and perinatal mortality and morbidity. Variants predisposing to pre-eclampsia might be under negative evolutionary selection that is likely to keep their population frequencies low. We exome sequenced samples from a hundred Finnish pre-eclamptic women in pools of ten to screen for low-frequency, large-effect risk variants for pre-eclampsia. After filtering and additional genotyping steps, we selected 28 low-frequency... -
Interaction between rs10830963 polymorphism in MTNR1B and lifestyle intervention on occurrence of gestational diabetes
CONCLUSIONS/INTERPRETATION: In women at high risk of GDM, only those not carrying the risk allele G benefited from the lifestyle intervention. Our results indicate that certain genetic risk variants may modify the effectiveness of lifestyle interventions. This may provide important information when planning GDM prevention studies in the future. -
Preeclampsia does not share common risk alleles in 9p21 with coronary artery disease and type 2 diabetes
CONCLUSIONS: Our study did not find evidence for the involvement of the 9p21 region in the risk of preeclampsia. Key Message Chromosome 9p21 is not associated with preeclampsia. -
Extending the scope of pooled analyses of individual patient biomarker data from heterogeneous laboratory platforms and cohorts using merging algorithms
CONCLUSIONS: We demonstrate the feasibility of merging PlGF concentrations from different analytical platforms. Overall BRC identification of HDP performed at least as well as platform-specific curves. Our method can be extended to any set of biomarkers obtained from different laboratory platforms in any field. Merged biomarker data from multiple studies will improve statistical power and enlarge our understanding of the pathophysiology and management of medical syndromes. -
Maternal Prenatal Positive Affect, Depressive and Anxiety Symptoms and Birth Outcomes: The PREDO Study
CONCLUSIONS: This study with 14 measurements of maternal emotions during pregnancy show modest effects of prenatal emotions during the third pregnancy trimester, particularly in the weeks close to delivery, on gestational length. From the clinical perspective, the effects were negligible. No associations were detected between prenatal emotions and birth weight. -
Collaboration to Understand Complex Diseases: Preeclampsia and Adverse Pregnancy Outcomes
No abstract -
The Salivary Scavenger and Agglutinin (SALSA) in Healthy and Complicated Pregnancy
Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality worldwide. The etiology is not clear, but an immune attack towards components of placenta or fetus has been indicated. This involves activation of the complement system in the placenta. We have previously described the presence of the complement-regulating protein salivary scavenger and agglutinin (SALSA) in amniotic fluid. In this study we investigated the potential role of SALSA in pregnancy by analyzing its... -
Heterogeneity of maternal characteristics and impact on gestational diabetes (GDM) risk-Implications for universal GDM screening?
CONCLUSION: Despite a healthier metabolic profile at baseline the non-obese women with a history of GDM displayed a markedly higher cumulative incidence of GDM. GWG and the presence of diabetes-associated antibodies were not associated with GDM occurrence among these high-risk women. Key message Despite a healthier metabolic profile at baseline the non-obese women with previous gestational diabetes mellitus display a markedly higher cumulative incidence of gestational diabetes mellitus. -
Corrigendum: Gene expression profiling of pre-eclamptic placentae by RNA sequencing
No abstract -
White's classification and pregnancy outcome in women with type 1 diabetes: a population-based cohort study
CONCLUSIONS/INTERPRETATION: White's classification is useful in estimating the risk of pre-eclampsia in early pregnancy independently of suboptimal glycaemic control and hypertension. However, its utility in predicting adverse perinatal outcomes seems limited when information on first trimester HbA1c, blood pressure and diabetic microvascular complications is available. -
Gestational Diabetes Mellitus Can Be Prevented by Lifestyle Intervention: The Finnish Gestational Diabetes Prevention Study (RADIEL): A Randomized Controlled Trial
CONCLUSIONS: A moderate individualized lifestyle intervention reduced the incidence of GDM by 39% in high-risk pregnant women. These findings may have major health consequences for both the mother and the child.