Publications
2026
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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... -
Genotype-Dependent Effects of Mechanical Stretch and GATA4-Targeted Compound 3i-1262 in Cardiomyopathy Patient-Derived hiPSC-Cardiomyocytes
Genetic hypertrophic and dilated cardiomyopathies (HCM and DCM, respectively) are characterised by structural and functional abnormalities that can lead to heart failure. However, current therapies mainly reduce symptoms. Patient-derived human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes provide a valuable platform to study genotype-specific pathophysiology and pharmacology. We subjected hiPSC-cardiomyocytes from healthy individuals and from patients carrying pathogenic MYBPC3... -
Metabolic fatty acid substrates enhance the structural and mechanical performance of human-induced pluripotent stem cell-derived cardiomyocytes
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer a powerful platform for disease modeling, drug discovery, and regenerative therapies. However, their clinical and research utility remains limited by their immature, fetal-like phenotype. In the human heart, postnatal metabolic maturation involves a critical switch from glycolysis to fatty acid β-oxidation, enabling efficient ATP production via oxidative phosphorylation. In this study, we investigated whether mimicking... -
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. -
Luminescence lifetime imaging integrated into selective plane illumination microscopy for oxygen imaging in 3D cell cultures
There is a growing need for 3D imaging that records not only cellular structures but also key chemical parameters, such as local oxygen tension or pH within 3D cell cultures. To meet this need, we have designed and developed a 3D luminescence microscopy platform that combines two microscopy modalities: selective plane illumination microscopy (SPIM) and luminescence lifetime imaging microscopy (LLIM). The SPIM-LLIM combination enables rapid 3D imaging with low phototoxicity and versatile use of... -
Human cardiac innervation-on-a-chip platform recapitulates neurocardiac interactions and supports future disease modeling
The cardiac autonomic nervous system regulates cardiac function through innervation, and dysfunction of the neuronal and cardiovascular crosstalk has been linked to various pathologies. Here, we present a cardiac innervation-on-a-chip model by combining human induced pluripotent stem cell (hiPSC)-derived cortical neurons, postganglionic sympathetic neurons, and ventricular cardiomyocytes in a compartmentalized microfluidic device called a 3D3C chip to generate physiologically relevant in vitro... -
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... -
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... -
Unveiling cellular mechanisms underlying MYZAP related dilated cardiomyopathy using patient specific hiPSC cardiomyocytes
Dilated cardiomyopathy (DCM) remains a leading cause of heart failure lacking effective treatments. Despite clinical advances, its pathogenic mechanisms are diverse and unclear. Recent attention has increasingly focused on the intercalated disc (ID), a specialized structure essential for mechanical and electrical coupling between cardiomyocytes and implicated in hereditary cardiomyopathies. MYZAP, an ID protein involved in SRF signalling, directly interacts with key ID components including DSP,... -
Organobodies: a robust and size-controllable system for generating scalable hiPSC-derived liver organoids for drug toxicity screening
Human hepatic organoids derived from pluripotent or adult stem cells offer powerful platforms for disease modeling and drug discovery. However, developing robust and scalable organoids capable of sustaining long-term functionality remains challenging. Here, we developed a novel, semi-defined approach using a self-assembling peptide and collagen I to create highly uniform human induced pluripotent stem cell-derived hepatic organoids in droplet format, which we term hepatic organobodies (OBs).... -
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.
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. -
A hypoxia-on-a-chip platform for modeling ischemic arrhythmogenesis and evaluating the effects of levosimendan and OR-1896 on ischemic human iPSC-derived cardiomyocytes
Acute hypoxia is a major contributor to cardiomyocyte damage and dysfunction in ischemic heart disease, and the effective therapeutic strategies remain limited. Levosimendan, a calcium sensitizer with both inotropic and vasodilatory effects, along with its active metabolite OR-1896, is utilized in the treatment of acute heart failure. In this study, we investigated the cardioprotective and antiarrhythmic effects of levosimendan and its metabolite OR-1896 under hypoxic conditions using... -
Artificial intelligence applications in hypertrophic cardiomyopathy: turns and loopholes
Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease where, despite recent advances, accurate diagnosis, risk stratification, and personalized treatment remain challenging. Artificial intelligence (AI) offers a transformative approach to HCM by enabling rapid, precise analysis of complex data. This article reviews the current and potential applications of AI in HCM. AI enhances diagnostic accuracy by analysing electrocardiograms, echocardiography, and cardiac magnetic resonance images,... -
QT and RR interval analysis in genetic cardiac diseases using the AccuQT and advanced heart rate variability methods
The QT interval is a key indicator in assessing arrhythmia risk, evaluating drug safety, and supporting clinical diagnosis in cardiology. The QT interval is significantly influenced by heart rate so it must be accurately corrected to ensure reliable clinical interpretation. Conventional correction formulas, such as Bazett's formula, are widely utilized but often criticized for inaccuracies, either under- or overcorrecting QT intervals in different physiological conditions. The recently developed... -
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... -
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. -
An <em>in vivo</em> mimetic liver-lobule-chip (LLoC) for stem cell maturation, and zonation of hepatocyte-like cells on chip
In vitro cell culture models play a crucial role in preclinical drug discovery. To achieve optimal culturing environments and establish physiologically relevant organ-specific conditions, it is imperative to replicate in vivo scenarios when working with primary or induced pluripotent cell types. However, current approaches to recreating in vivo conditions and generating relevant 3D cell cultures still fall short. In this study, we validate a liver-lobule-chip (LLoC) containing 21 artificial... -
Compartmentalized perfusion for temporal control of the chemical microenvironment of iPSC-derived cardiac cells
Organ-on-chip structures are predicted to have a significant influence in drug research. In these structures, perfusion can provide cells a more controllable environment to receive signaling molecules. In many current organ-on-chip applications, perfusion is used for shear stress stimulus for the cells, but it can also provide a more precise way of controlling the chemical microenvironment around the cells. In this paper, we propose an open-top organ-on-chip structure with compartment-specific... -
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... -
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. -
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.
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. -
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... -
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,... -
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... -
Relevance of accurate QT correction in the assessment of long QT syndrome
CONCLUSION: The selected QT correction method is important in the identification of LQTS. In particular, the use of Bazett correction should be questioned. Fridericia correction yields good results with respect to its simplicity. AccuQT has the best accuracy out of all the methods for LQTS discrimination. For practical applicability, however, AccuQT needs further validation in realistic clinical conditions. -
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). -
Gellan gum-gelatin based cardiac models support formation of cellular networks and functional cardiomyocytes
Cardiovascular diseases remain as the most common cause of death worldwide. To reveal the underlying mechanisms in varying cardiovascular diseases, in vitro models with cells and supportive biomaterial can be designed to recapitulate the essential components of human heart. In this study, we analyzed whether 3D co-culture of cardiomyocytes (CM) with vascular network and with adipose tissue-derived mesenchymal stem/stromal cells (ASC) can support CM functionality. CM were cultured with either... -
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... -
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. -
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...
2023
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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... -
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... -
Therapy Efficacy of Idiopathic Ventricular Extrasystoles: A Real Life Study
CONCLUSIONS: For a symptomatic patient, catheter ablation is an effective and often fully curative treatment. The success rate was similar regardless of the site of VESs. This suggests that catheter ablation should also be assessed early on for other cases besides classic right ventricular outflow tract VESs. A high BMI was the only factor associated with a poor procedure success rate. The procedure itself is safe, and adverse effects are rare. The radiation dose is also low partly due to the... -
Improvements in Maturity and Stability of 3D iPSC-Derived Hepatocyte-like Cell Cultures
Induced pluripotent stem cell (iPSC) technology enables differentiation of human hepatocytes or hepatocyte-like cells (iPSC-HLCs). Advances in 3D culturing platforms enable the development of more in vivo-like liver models that recapitulate the complex liver architecture and functionality better than traditional 2D monocultures. Moreover, within the liver, non-parenchymal cells (NPCs) are critically involved in the regulation and maintenance of hepatocyte metabolic function. Thus, models... -
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.... -
The Junctophilin-2 Mutation p.(Thr161Lys) Is Associated with Hypertrophic Cardiomyopathy Using Patient-Specific iPS Cardiomyocytes and Demonstrates Prolonged Action Potential and Increased Arrhythmogenicity
Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases; it is primarily caused by mutations in sarcomeric genes. However, HCM is also associated with mutations in non-sarcomeric proteins and a Finnish founder mutation for HCM in non-sarcomeric protein junctophilin-2 (JPH2) has been identified. This study aimed at assessing the issue of modelling the rare Finnish founder mutation in cardiomyocytes (CMs) differentiated from iPSCs; therefore, presenting the same... -
Data Resource Profile: Nationwide registry data for high-throughput epidemiology and machine learning (FinRegistry)
No abstract -
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. -
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... -
HiPSC-derived cardiomyocyte to model Brugada syndrome: both asymptomatic and symptomatic mutation carriers reveal increased arrhythmogenicity
Brugada syndrome is an inherited cardiac arrhythmia disorder that is mainly associated with mutations of the cardiac voltage-gated sodium channel alpha subunit 5 (SCN5A) gene. The clinical symptoms include ventricular fibrillation and an increased risk of sudden cardiac death. Human-induced pluripotent stem cell (hiPSC) lines were derived from symptomatic and asymptomatic individuals carrying the R1913C mutation in the SCN5A gene. The present work aimed to observe the phenotype-specific... -
Accurate QT correction method from transfer entropy
CONCLUSION: AccuQT has significant potential to become the QTc method of choice in clinical studies and drug development. The method can be implemented in any device recording R-R and QT intervals. -
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.... -
Coronary artery disease patient-derived iPSC-hepatocytes have distinct miRNA profile that may alter lipid metabolism
Metabolic dysfunction, partly driven by altered liver function, predisposes to coronary artery disease (CAD), but the role of liver in vulnerable atherosclerotic plaque development remains unclear. Here we produced hepatocyte-like cells (HLCs) from 27 induced pluripotent stem cell (iPSC) lines derived from 15 study subjects with stable CAD (n = 5), acute CAD (n = 5) or healthy controls (n = 5). We performed a miRNA microarray screening throughout the differentiation, as well as compared... -
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... -
Fluorescent hiPSC-derived MYH6-mScarlet cardiomyocytes for real-time tracking, imaging, and cardiotoxicity assays
Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) hold great potential in the cardiovascular field for human disease modeling, drug development, and regenerative medicine. However, multiple hurdles still exist for the effective utilization of hiPSC-CMs as a human-based experimental platform that can be an alternative to the current animal models. To further expand their potential as a research tool and bridge the translational gap, we have generated a cardiac-specific hiPSC...
2022
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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... -
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... -
Accurate QT correction method from transfer entropy
CONCLUSION: AccuQT has significant potential to become the QTc method of choice in clinical studies and drug development. The method can be implemented in any device recording R-R and QT intervals. -
Electrophysiological Changes of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes during Acute Hypoxia and Reoxygenation
Ischemic heart disease is the most common cardiovascular disease and a major burden for healthcare worldwide. However, its pathophysiology is still not fully understood, and human-based models for disease mechanisms and treatments are needed. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to model acute ischemia-reperfusion in our novel cell culture assembly. The assembly enables exchange of oxygen partial pressure for the cells within minutes, mimicking... -
Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations
Mutations in the lamin A/C gene (LMNA) cause dilated cardiomyopathy associated with increased activity of ERK1/2 in the heart. We recently showed that ERK1/2 phosphorylates cofilin-1 on threonine 25 (phospho(T25)-cofilin-1) that in turn disassembles the actin cytoskeleton. Here, we show that in muscle cells carrying a cardiomyopathy-causing LMNA mutation, phospho(T25)-cofilin-1 binds to myocardin-related transcription factor A (MRTF-A) in the cytoplasm, thus preventing the stimulation of serum... -
Sex differences in heart: from basics to clinics
Sex differences exist in the structure and function of human heart. The patterns of ventricular repolarization in normal electrocardiograms (ECG) differ in men and women: men ECG pattern displays higher T-wave amplitude and increased ST angle. Generally, women have longer QT duration because of reduced repolarization reserve, and thus, women are more susceptible for the occurrence of torsades de pointes associated with drugs prolonging ventricular repolarization. Sex differences are also... -
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. -
Fluorescent hiPSC-derived MYH6-mScarlet cardiomyocytes for real-time tracking, imaging, and cardiotoxicity assays
Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) hold great potential in the cardiovascular field for human disease modeling, drug development, and regenerative medicine. However, multiple hurdles still exist for the effective utilization of hiPSC-CMs as a human-based experimental platform that can be an alternative to the current animal models. To further expand their potential as a research tool and bridge the translational gap, we have generated a cardiac-specific hiPSC... -
Cardiac Ischemia On-a-Chip: Antiarrhythmic Effect of Levosimendan on Ischemic Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Ischemic heart disease (IHD) is one of the leading causes of mortality worldwide. Preserving functionality and preventing arrhythmias of the heart are key principles in the management of patients with IHD. Levosimendan, a unique calcium (Ca^(2+)) enhancer with inotropic activity, has been introduced into clinical usage for heart failure treatment. Human-induced pluripotent cell-derived cardiomyocytes (hiPSC-CMs) offer an opportunity to better understand the pathophysiological mechanisms of the... -
Human Neurons Form Axon-Mediated Functional Connections with Human Cardiomyocytes in Compartmentalized Microfluidic Chip
The cardiac autonomic nervous system (cANS) regulates cardiac function by innervating cardiac tissue with axons, and cardiomyocytes (CMs) and neurons undergo comaturation during the heart innervation in embryogenesis. As cANS is essential for cardiac function, its dysfunctions might be fatal; therefore, cardiac innervation models for studying embryogenesis, cardiac diseases, and drug screening are needed. However, previously reported neuron-cardiomyocyte (CM) coculture chips lack studies of... -
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).... -
Toward Xeno-Free Differentiation of Human Induced Pluripotent Stem Cell-Derived Small Intestinal Epithelial Cells
The small intestinal epithelium has an important role in nutrition, but also in drug absorption and metabolism. There are a few two-dimensional (2D) patient-derived induced pluripotent stem cell (iPSC)-based intestinal models enabling easy evaluation of transcellular transport. It is known that animal-derived components induce variation in the experimental outcomes. Therefore, we aimed to refine the differentiation protocol by using animal-free components. More specifically, we compared... -
Data analytics for cardiac diseases
In the present research we tackled the classification of seven genetic cardiac diseases and control subjects by using an extensive set of machine learning algorithms with their variations from simple K-nearest neighbor searching method to support vector machines. The research was based on calcium transient signals measured from induced pluripotent stem cell-derived cardiomyocytes. All in all, 55 different machine learning alternatives were used to model eight classes by applying the principle of...
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... -
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. -
Toward Xeno-Free Differentiation of Human Induced Pluripotent Stem Cell-Derived Small Intestinal Epithelial Cells
The small intestinal epithelium has an important role in nutrition, but also in drug absorption and metabolism. There are a few two-dimensional (2D) patient-derived induced pluripotent stem cell (iPSC)-based intestinal models enabling easy evaluation of transcellular transport. It is known that animal-derived components induce variation in the experimental outcomes. Therefore, we aimed to refine the differentiation protocol by using animal-free components. More specifically, we compared... -
On computational classification of genetic cardiac diseases applying iPSC cardiomyocytes
CONCLUSIONS: Despite more complex classification tasks compared to our earlier research and having more different genetic cardiac diseases in the analysis, it is still possible to attain good disease classification results. As excepted, leave-one-out test and 10-fold cross-validation achieved virtually equal results. -
Methylation status of nc886 epiallele reflects periconceptional conditions and is associated with glucose metabolism through nc886 RNAs
CONCLUSIONS: These results indicate that nc886 metastable epiallele methylation is tuned by the periconceptional conditions and it associates with glucose metabolism through the expression of the ncRNAs coded in the epiallele region. -
Human induced pluripotent stem cell-based platform for modeling cardiac ischemia
Ischemic heart disease is a major cause of death worldwide, and the only available therapy to salvage the tissue is reperfusion, which can initially cause further damage. Many therapeutics that have been promising in animal models have failed in human trials. Thus, functional human based cardiac ischemia models are required. In this study, a human induced pluripotent stem cell derived-cardiomyocyte (hiPSC-CM)-based platform for modeling ischemia-reperfusion was developed utilizing a system... -
Electrophysiological evaluation of human induced pluripotent stem cell-derived cardiomyocytes obtained by different methods
The human induced pluripotent stem cells (hiPSCs) derived cardiomyocytes (CMs) (hiPSC-CMs) retain the same genetic information as the donor, and they have been shown to faithfully recapitulate the disease phenotypes of various genetic cardiac diseases. The hiPSC-CMs can be utilized in multiple types of studies and in most cases, the functionality of hiPSC-CMs is of interest. For the functional analyses, the hiPSC-CMs need to be manipulated after differentiation, e.g. enriched or dissociated into... -
Analysis of Drug Effects on iPSC Cardiomyocytes with Machine Learning
Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer an attractive experimental platform to investigate cardiac diseases and therapeutic outcome. In this study, iPSC-CMs were utilized to study their calcium transient signals and drug effects by means of machine learning, a central part of artificial intelligence. Drug effects were assessed in six iPSC-lines carrying different mutations causing catecholaminergic polymorphic ventricular tachycardia (CPVT), a...
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... -
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. -
Methylation status of nc886 epiallele reflects periconceptional conditions and is associated with glucose metabolism through nc886 RNAs
CONCLUSIONS: These results indicate that nc886 metastable epiallele methylation is tuned by the periconceptional conditions and it associates with glucose metabolism through the expression of the ncRNAs coded in the epiallele region. -
Different rates of flux through the biosynthetic pathway for long-chain versus very-long-chain sphingolipids
The backbone of all sphingolipids (SLs) is a sphingoid long-chain base (LCB) to which a fatty acid is N-acylated. Considerable variability exists in the chain length and degree of saturation of both of these hydrophobic chains, and recent work has implicated ceramides with different LCBs and N-acyl chains in distinct biological processes; moreover, they may play different roles in disease states and possibly even act as prognostic markers. We now demonstrate that the half-life, or turnover rate,... -
Covalent immobilization of luminescent oxygen indicators reduces cytotoxicity
Luminescence-based oxygen sensing is a widely used tool in cell culture applications. In a typical configuration, the luminescent oxygen indicators are embedded in a solid, oxygen-permeable matrix in contact with the culture medium. However, in sensitive cell cultures even minimal leaching of the potentially cytotoxic indicators can become an issue. One way to prevent the leaching is to immobilize the indicators covalently into the supporting matrix. In this paper, we report on a method where... -
hiPSC-Derived Cardiomyocyte Model of LQT2 Syndrome Derived from Asymptomatic and Symptomatic Mutation Carriers Reproduces Clinical Differences in Aggregates but Not in Single Cells
Mutations in the HERG gene encoding the potassium ion channel HERG, represent one of the most frequent causes of long QT syndrome type-2 (LQT2). The same genetic mutation frequently presents different clinical phenotypes in the family. Our study aimed to model LQT2 and study functional differences between the mutation carriers of variable clinical phenotypes. We derived human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) from asymptomatic and symptomatic HERG mutation carriers... -
Analysis of Drug Effects on iPSC Cardiomyocytes with Machine Learning
Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer an attractive experimental platform to investigate cardiac diseases and therapeutic outcome. In this study, iPSC-CMs were utilized to study their calcium transient signals and drug effects by means of machine learning, a central part of artificial intelligence. Drug effects were assessed in six iPSC-lines carrying different mutations causing catecholaminergic polymorphic ventricular tachycardia (CPVT), a... -
Separation of HCM and LQT Cardiac Diseases with Machine Learning of Ca2+ Transient Profiles
CONCLUSION: The results indicate that the methods applied would be efficient for the identification of these genetic cardiac diseases. -
DSP p.(Thr2104Glnfs*12) variant presents variably with early onset severe arrhythmias and left ventricular cardiomyopathy
CONCLUSIONS: The patients diagnosed with DCM showed an arrhythmogenic phenotype as well as SCD at young age supporting the recently proposed concept of arrhythmogenic cardiomyopathy. This study also demonstrates relatively low penetrance of truncating DSP variant in the probands' family members by the age of 40. Further studies are needed to elucidate the possible relations between myocardial inflammation and pathogenic DSP variants. -
Co-culture of human induced pluripotent stem cell-derived retinal pigment epithelial cells and endothelial cells on double collagen-coated honeycomb films
In vitro cell culture models representing the physiological and pathological features of the outer retina are urgently needed. Artificial tissue replacements for patients suffering from degenerative retinal diseases are similarly in great demand. Here, we developed a co-culture system based solely on the use of human induced pluripotent stem cell (hiPSC)-derived cells. For the first time, hiPSC-derived retinal pigment epithelium (RPE) and endothelial cells (EC) were cultured on opposite sides of... -
Pneumatic unidirectional cell stretching device for mechanobiological studies of cardiomyocytes
In this paper, we present a transparent mechanical stimulation device capable of uniaxial stimulation, which is compatible with standard bioanalytical methods used in cellular mechanobiology. We validate the functionality of the uniaxial stimulation system using human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs). The pneumatically controlled device is fabricated from polydimethylsiloxane (PDMS) and provides uniaxial strain and superior optical performance compatible with...
2019
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Unveiling cellular mechanisms underlying MYZAP related dilated cardiomyopathy using patient specific hiPSC cardiomyocytes
Dilated cardiomyopathy (DCM) remains a leading cause of heart failure lacking effective treatments. Despite clinical advances, its pathogenic mechanisms are diverse and unclear. Recent attention has increasingly focused on the intercalated disc (ID), a specialized structure essential for mechanical and electrical coupling between cardiomyocytes and implicated in hereditary cardiomyopathies. MYZAP, an ID protein involved in SRF signalling, directly interacts with key ID components including DSP,... -
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... -
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. -
Separation of HCM and LQT Cardiac Diseases with Machine Learning of Ca2+ Transient Profiles
CONCLUSION: The results indicate that the methods applied would be efficient for the identification of these genetic cardiac diseases. -
Co-culture of human induced pluripotent stem cell-derived retinal pigment epithelial cells and endothelial cells on double collagen-coated honeycomb films
In vitro cell culture models representing the physiological and pathological features of the outer retina are urgently needed. Artificial tissue replacements for patients suffering from degenerative retinal diseases are similarly in great demand. Here, we developed a co-culture system based solely on the use of human induced pluripotent stem cell (hiPSC)-derived cells. For the first time, hiPSC-derived retinal pigment epithelium (RPE) and endothelial cells (EC) were cultured on opposite sides of... -
Pneumatic unidirectional cell stretching device for mechanobiological studies of cardiomyocytes
In this paper, we present a transparent mechanical stimulation device capable of uniaxial stimulation, which is compatible with standard bioanalytical methods used in cellular mechanobiology. We validate the functionality of the uniaxial stimulation system using human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs). The pneumatically controlled device is fabricated from polydimethylsiloxane (PDMS) and provides uniaxial strain and superior optical performance compatible with... -
Compromised Barrier Function in Human Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells from Type 2 Diabetic Patients
In diabetic patients, high blood glucose induces alterations in retinal function and can lead to visual impairment due to diabetic retinopathy. In immortalized retinal pigment epithelial (RPE) cultures, high glucose concentrations are shown to lead to impairment in epithelial barrier properties. For the first time, the induced pluripotent stem-cell-derived retinal pigment epithelium (hiPSC-RPE) cell lines derived from type 2 diabetics and healthy control patients were utilized to assess the... -
Dedifferentiation of Primary Hepatocytes is Accompanied with Reorganization of Lipid Metabolism Indicated by Altered Molecular Lipid and miRNA Profiles
CONCLUSION: Our results showed major alterations in the molecular lipid species profiles, lipid-metabolizing enzyme expression as wells as miRNA profiles of the PHHs during their prolonged culture, which in concert could play important roles in the PHHs' loss of phenotype. These findings promote the understanding from the dedifferentiation process and could help in developing optimal culture conditions, which better meet the needs of the PHHs and support their original phenotype. -
Modeling of <em>LMNA</em>-Related Dilated Cardiomyopathy Using Human Induced Pluripotent Stem Cells
Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure and heart transplantation. A portion of familial DCM is due to mutations in the LMNA gene encoding the nuclear lamina proteins lamin A and C and without adequate treatment these patients have a poor prognosis. To get better insights into pathobiology behind this disease, we focused on modeling LMNA-related DCM using human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM). Primary skin fibroblasts from DCM... -
Polyethylene Terephthalate Textiles Enhance the Structural Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have the potential to serve as a model for human cardiomyocytes. However, hiPSC-CMs are still considered immature. CMs differentiated from hiPSCs more resemble fetal than adult cardiomyocytes. Putative factors enhancing maturation include in vitro culture duration, culture surface topography, and mechanical, chemical, and electrical stimulation. Stem cell-derived cardiomyocytes are traditionally cultured on glass surfaces... -
Mechanically Biomimetic Gelatin-Gellan Gum Hydrogels for 3D Culture of Beating Human Cardiomyocytes
To promote the transition of cell cultures from 2D to 3D, hydrogels are needed to biomimic the extracellular matrix (ECM). One potential material for this purpose is gellan gum (GG), a biocompatible and mechanically tunable hydrogel. However, GG alone does not provide attachment sites for cells to thrive in 3D. One option for biofunctionalization is the introduction of gelatin, a derivative of the abundant ECM protein collagen. Unfortunately, gelatin lacks cross-linking moieties, making the... -
Scaling and correlation properties of RR and QT intervals at the cellular level
We study complex scaling properties of RR and QT intervals of electrocardiograms (ECGs) with their equivalences at the cellular level, that is, inter-beat intervals (IBI) and field potential durations (FPD) of spontaneously beating human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) aggregates. Our detrended fluctuation analysis and Poincaré plots reveal remarkable similarities between the ECG and hiPSC-CM data. In particular, no statistically significant difference was found in... -
Extensive reprogramming of the nascent transcriptome during iPSC to hepatocyte differentiation
Hepatocyte-like cells (HLCs) derived from induced pluripotent stem cells (iPSCs) provide a renewable source of cells for drug discovery, disease modelling and cell-based therapies. Here, by using GRO-Seq we provide the first genome-wide analysis of the nascent RNAs in iPSCs, HLCs and primary hepatocytes to extend our understanding of the transcriptional changes occurring during hepatic differentiation process. We demonstrate that a large fraction of hepatocyte-specific genes are regulated at... -
Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy
CONCLUSIONS: We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM-related mutations in non-sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM-related deaths annually. -
hiPSC-derived hepatocytes closely mimic the lipid profile of primary hepatocytes: A future personalised cell model for studying the lipid metabolism of the liver
Hepatocyte-like cells (HLCs) differentiated from human-induced pluripotent stem cells offer an alternative platform to primary human hepatocytes (PHHs) for studying the lipid metabolism of the liver. However, despite their great potential, the lipid profile of HLCs has not yet been characterized. Here, we comprehensively studied the lipid profile and fatty acid (FA) metabolism of HLCs and compared them with the current standard hepatocyte models: HepG2 cells and PHHs. We differentiated HLCs by...
2018
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Unveiling cellular mechanisms underlying MYZAP related dilated cardiomyopathy using patient specific hiPSC cardiomyocytes
Dilated cardiomyopathy (DCM) remains a leading cause of heart failure lacking effective treatments. Despite clinical advances, its pathogenic mechanisms are diverse and unclear. Recent attention has increasingly focused on the intercalated disc (ID), a specialized structure essential for mechanical and electrical coupling between cardiomyocytes and implicated in hereditary cardiomyopathies. MYZAP, an ID protein involved in SRF signalling, directly interacts with key ID components including DSP,... -
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... -
Therapy Efficacy of Idiopathic Ventricular Extrasystoles: A Real Life Study
CONCLUSIONS: For a symptomatic patient, catheter ablation is an effective and often fully curative treatment. The success rate was similar regardless of the site of VESs. This suggests that catheter ablation should also be assessed early on for other cases besides classic right ventricular outflow tract VESs. A high BMI was the only factor associated with a poor procedure success rate. The procedure itself is safe, and adverse effects are rare. The radiation dose is also low partly due to the... -
Information transfer in QT-RR dynamics: Application to QT-correction
The relation between the electrical properties of the heart and the beating rate is essential for the heart functioning. This relation is central when calculating the "corrected QT interval" - an important measure of the risk of potentially lethal arrhythmias. We use the transfer entropy method from information theory to quantitatively study the mutual dynamics of the ventricular action potential duration (the QT interval) and the length of the beat-to-beat (RR) interval. We show that for... -
Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure
During the last two decades, mutations in sarcomere genes have found to comprise the most common cause for hypertrophic cardiomyopathy (HCM), but still significant number of patients with dominant HCM in the family are left without molecular genetic diagnosis. Next generation sequencing (NGS) does not only enable evaluation of established HCM genes but also candidate genes for cardiomyopathy are frequently tested which may lead to a situation where conclusive interpretation of the variant... -
hiPSC-derived hepatocytes closely mimic the lipid profile of primary hepatocytes: A future personalised cell model for studying the lipid metabolism of the liver
Hepatocyte-like cells (HLCs) differentiated from human-induced pluripotent stem cells offer an alternative platform to primary human hepatocytes (PHHs) for studying the lipid metabolism of the liver. However, despite their great potential, the lipid profile of HLCs has not yet been characterized. Here, we comprehensively studied the lipid profile and fatty acid (FA) metabolism of HLCs and compared them with the current standard hepatocyte models: HepG2 cells and PHHs. We differentiated HLCs by... -
Automatic Optimization of an <em>in Silico</em> Model of Human iPSC Derived Cardiomyocytes Recapitulating Calcium Handling Abnormalities
The growing importance of human induced pluripotent stem cell-derived cardiomyoyctes (hiPSC-CMs), as patient-specific and disease-specific models for studying cellular cardiac electrophysiology or for preliminary cardiotoxicity tests, generated better understanding of hiPSC-CM biophysical mechanisms and great amount of action potential and calcium transient data. In this paper, we propose a new hiPSC-CM in silico model, with particular attention to Ca^(2+) handling. We used (i) the hiPSC-CM... -
Simultaneous recordings of action potentials and calcium transients from human induced pluripotent stem cell derived cardiomyocytes
Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) offer a unique in vitro platform to study cardiac diseases, as they recapitulate many disease phenotypes. The membrane potential (V(m)) and intracellular calcium (Ca^(2+)) transient (CaT) are usually investigated separately, because incorporating different techniques to acquire both aspects concurrently is challenging. In this study, we recorded V(m) and CaT simultaneously to understand the interrelation between these... -
Detection of genetic cardiac diseases by Ca<sup>2+</sup> transient profiles using machine learning methods
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have revolutionized cardiovascular research. Abnormalities in Ca^(2+) transients have been evident in many cardiac disease models. We have shown earlier that, by exploiting computational machine learning methods, normal Ca^(2+) transients corresponding to healthy CMs can be distinguished from diseased CMs with abnormal transients. Here our aim was to study whether it is possible to separate different genetic cardiac diseases... -
A Portable Microscale Cell Culture System with Indirect Temperature Control
A physiologically relevant environment is essential for successful long-term cell culturing in vitro. Precise control of temperature, one of the most crucial environmental parameters in cell cultures, increases the fidelity and repeatability of the experiments. Unfortunately, direct temperature measurement can interfere with the cultures or prevent imaging of the cells. Furthermore, the assessment of dynamic temperature variations in the cell culture area is challenging with the methods... -
Age Is Relative-Impact of Donor Age on Induced Pluripotent Stem Cell-Derived Cell Functionality
Induced pluripotent stem cells (iPSCs) avoid many of the restrictions that hamper the application of human embryonic stem cells: limited availability of source material due to legal restrictions in some countries, immunogenic rejection and ethical concerns. Also, the donor's clinical phenotype is often known when working with iPSCs. Therefore, iPSCs seem ideal to tackle the two biggest tasks of regenerative medicine: degenerative diseases with genetic cause (e.g., Duchenne's muscular dystrophy)... -
Divergent effects of adrenaline in human induced pluripotent stem cell-derived cardiomyocytes obtained from hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease that affects the heart muscle with diverse clinical outcomes. HCM can cause sudden cardiac death (SCD) during or immediately after mild to rigorous physical activity in young patients. However, the mechanism causing SCD as a result of exercise remains unknown, but exercise-induced ventricular arrhythmias are thought to be responsible for this fatal consequence. To understand the disease mechanism behind HCM in a better way,...