Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with

Background - TTN, the largest gene in the human body, encodes titin (TTN), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN, particularly truncating variants (TTNtvs), have been implicated in the pathogenicity of cardiomyopathy (CM). Despite this link, there is also a high burden of TTNtvs in the ostensibly healthy general population

Background - Human heterotaxy is a group of congenital disorders characterized by misplacement of one or more organs according to the left-right axis. The genetic causes of human heterotaxy are highly heterogeneous.Methods - We performed exome sequencing in a cohort of 26 probands with heterotaxy followed by gene burden analysis for the enrichment of novel rare damaging mutations. Transcription activator-like

Background - Individual risk prediction based on genome-wide polygenic risk scores (PRS) utilizing millions of genetic variants has attracted much attention. It is under debate whether PRS models can be applied - without loss of precision - to populations of similar ethnic but different geographical background than the one the scores were trained on. Here, we examine how PRS trained in population-specific

Background - Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A

Background - Atrial fibrillation (AF) often arises from structural abnormalities in the left atria (LA). Annotation of the non-coding genome in human LA is limited, as are effects on gene expression and chromatin architecture. Many AF-associated genetic variants reside in noncoding regions; this knowledge gap impairs efforts to understand the molecular mechanisms of AF and cardiac conduction phenotypes

Background - Excess alcohol intake and inherited predisposition may increase risk of atrial fibrillation (AF). We assessed the association between alcohol intake, polygenic predisposition to AF, and incident AF in the UK Biobank, a prospective cohort study.Methods - In 376,776 UK Biobank participants enrolled between 2006-2010, we tested alcohol consumption (stratified by the Centers of Disease Control

Background - The X-linked Danon disease (DD) manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease (DD) in cardiomyopathy centers throughout Europe.Methods - Clinical and genetic data were collected in 16 cardiology centers from 8 European countries

Background - In the Women's Health Initiative hormone therapy (WHI-HT) trials, treatment with oral conjugated equine estrogens and medroxyprogesterone acetate (CEE+MPA) resulted in increased risk of coronary heart disease (CHD), while oral conjugated equine estrogens alone (CEE) did not.Methods - 481 metabolites were measured at baseline and at 1-year in 503 and 431 participants in the WHI CEE and

Background - In population-based research exome sequencing (ES), the path from variant discovery to return of results (rROR) is not well established. Variants discovered by research ES have the potential to improve population health.Methods - Population-based ES and agnostic ExWAS were performed 5,521 Amish individuals. Additional phenotyping and in vitro studies enabled reclassification of a KCNQ1

Background - Circulating biomarkers have been previously associated with atherosclerosis related risk factors, but the nature of these associations is incompletely understood.Methods - We performed multivariable-adjusted regressions and two-sample Mendelian randomization (MR) analyses to assess observational and causal associations of 27 circulating biomarkers with 7 cardiovascular traits in up to

Background - Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture

Background - The aortic valve is an important determinant of cardiovascular physiology and anatomic location of common human diseases.Methods - From a sample of 34,287 white British-ancestry participants, we estimated functional aortic valve area by planimetry from prospectively obtained cardiac MRI sequences of the aortic valve. Aortic valve area measurements were submitted to genome-wide association

Background:The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.Methods:Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian)

Background:Pathogenic variants in MYBPC3, encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped hypertrophic cardiomyopathy cohorts have precluded detailed genotype-phenotype correlations.Methods:Patients with hypertrophic cardiomyopathy and MYBPC3 variants were identified

Background:Whole-genome sequencing (WGS) costs are falling, yet, outside oncology, this information is seldom used in adult clinics. We piloted a rapid WGS (rWGS) workflow, focusing initially on estimating power for a feasibility study of introducing genome information into acute cardiovascular care.Methods:A prospective implementation study was conducted to test the feasibility and clinical utility

Background:Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency—homozygous loss-of-function (LoF) variants—in the ABCG5 or ABCG8 genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact

Background:To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry.Methods:We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies.Results:Singaporean HCM patients had significantly

Background:LMNA is a known causative gene of dilated cardiomyopathy and familial conduction disturbance. Nonsense-mediated mRNA decay, normally caused by nonsense mutations, is a safeguard process to protect cells from deleterious effects of inappropriate proteins from mutated genes. Nonsense-mediated mRNA decay induced by nonstop codon mutations is rare. We investigated the effect of an LMNA missense

Background:Cardiac troponin I (TNNI3) gene mutations account for 3% of hypertrophic cardiomyopathy and carriers have a heterogeneous phenotype, with increased risk of sudden cardiac death (SCD). Only one mutation (p.Arg21Cys) has been reported in the N terminus of the protein. In model organisms, it impairs PKA (protein kinase A) phosphorylation, increases calcium sensitivity, and causes diastolic

Background:Missense variants in the MYH7-encoded MYH7 (beta myosin heavy chain 7) represent a leading cause of hypertrophic cardiomyopathy (HCM). MYH7-specific American College of Medical Genetics and Genomics (ACMG) variant classification guidelines were released recently but have yet to be assessed independently. We set out to assess the performance of the MYH7-specific ACMG guidelines and determine

Background:Sequence variation at chromosome 9p21.3 accounts for 20% of myocardial infarctions (MIs) in several populations. Whereas the risk conferred by the 9p21.3 locus appears to act independently of traditional risk factors, studies suggest that the association between 9p21.3 and MI is modified by glucose homeostasis and lifestyle. We examined if the 9p21.3 variant rs1333049, along with the previously

Background:The KCNH2-encoded Kv11.1 hERG (human ether-a-go-go related gene) potassium channel is a critical regulator of cardiomyocyte action potential duration (APD). The majority of type 2 long-QT syndrome (LQT2) stems from trafficking defective KCNH2 mutations. Recently, Food and Drug Administration-approved cystic fibrosis protein trafficking chaperone, lumacaftor, has been proposed as novel therapy

Background:Genetic analysis is a first-tier test in dilated cardiomyopathy (DCM). Electrical phenotypes are common in genetic DCM, but their exact contribution to the clinical course and outcome is unknown. We determined the prevalence of pathogenic gene variants in a large unselected DCM population and determined the role of electrical phenotypes in association with outcome.Methods:This study included

Background:Resistin, a protein linked with inflammation and cardiometabolic diseases, is one of few proteins for which genome-wide association studies consistently report variants within and near the coding gene (RETN). Here, we took advantage of the reduced linkage disequilibrium in African populations to infer genetic causality for circulating resistin levels by performing genome-wide association

Background:Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale.Methods:To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy

Background:Familial hypercholesterolemia (FH) is a common autosomal codominant genetic disorder, which causes elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Even among individuals with monogenic FH, there is substantial interindividual variability in LDL-C levels and risk of ASCVD. We assessed the influence

Background:Inherited cardiac conditions present with a wide range of symptoms and may even result in sudden cardiac death. Relatives of probands with a confirmed pathogenic genetic variant are advised predictive DNA testing to enable prevention and treatment. In 2 previous cohort studies of 115 probands with a pathogenic variant, family uptake of genetic counseling was assessed in the first year(s)

Background:Ischemic stroke is a devastating complication affecting children with sickle cell anemia. Genetic factors are likely to be important in determining the risk of stroke but are poorly defined.Methods:We have studied a cohort of 19 children who had an overt ischemic stroke before 4 years of age. We predicted genetic determinants of stroke would be more prominent in this group. We performed

Background:The blood metabolome incorporates cues from the environment and the host’s genetic background, potentially offering a holistic view of an individual’s health status.Methods:We have compiled a vast resource of proton nuclear magnetic resonance metabolomics and phenotypic data encompassing over 25 000 samples derived from 26 community and hospital-based cohorts.Results:Using this resource

Coagulation FX (factor X) is a serine protease that catalyzes the formation of fibrin clots. Although this maintains hemostasis, it can also result in pathological thrombi and emboli.1,2 FXa (activated FX) inhibitors are efficacious for preventing deep venous thrombosis, pulmonary embolism,1 and cardioembolic stroke related to nonvalvular atrial fibrillation.2 However, the efficacy of FXa inhibitors

Background - In this study, we aimed to investigate functional mechanisms underlying CAD loci, and find molecular biomarkers for CAD.Methods - We devised a multiomics data analysis approach based on Mendelian randomization and utilized it to search for molecular biomarkers causally associated with the risk of CAD within genomic regions known to be associated with CAD.Results - Through our CAD-centered

Background - Elastin insufficiency causes recurrent vascular stenoses. Hemizygous deletion of the elastin gene (ELN) causes Williams-Beuren syndrome (WBS), while single nucleotide variants in ELN cause non-syndromic supravalvar aortic stenosis (SVAS). Our objective was to compare cardiovascular disease outcomes in patients with WBS and non-syndromic SVAS.Methods - Patients (81 WBS, 42 non-syndromic

Background - Mutation/variant-site specific risk stratification in long-QT syndrome type 1 (LQT1) has been well investigated, but it is still challenging to adapt current enormous genomic information to clinical aspects caused by each mutation/variant. We assessed a novel variant-specific risk stratification in LQT1 patients.Methods - We classified a pathogenicity of 141 KCNQ1 variants among 927 LQT1

Background - Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes (T2D).Methods - To test whether this reflects differential genetic influences on CAD-risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66,643 subjects (27,708 with CAD and 24,259 with T2D). Variants showing apparent association with CAD in stratified analyses

Background:De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.Methods:We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease

Background:For most disease-related traits the magnitude of the contribution of genetic factors in adolescents remains unclear.Methods:Twenty continuous traits related to anthropometry, cardiovascular and renal function, metabolism, and inflammation were selected from the ongoing prospective Tracking Adolescents’ Individual Lives Survey cohort in the Netherlands with measurements of up to 5 waves from

Background:Abnormal QT interval responses to heart rate (QT dynamics) is an independent risk predictor for cardiovascular disease in patients, but its genetic basis and prognostic value in a population-based cohort have not been investigated.Methods:QT dynamics during exercise and recovery were derived in 56 643 individuals from UK Biobank without a history of cardiovascular events. Genome-wide association

Background:Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy. Although it is associated with high morbidity and mortality, the related ion channel gene variants in children have not been fully investigated. This study aimed to elucidate the ion channel genetic landscape of LVNC and identify genotype-phenotype correlations in a large Japanese cohort.Methods:We enrolled 206

Background:Dilated cardiomyopathy (DCM) is a genetically heterogeneous cardiac disease characterized by progressive ventricular enlargement and reduced systolic function. Here, we report genetic and functional analyses implicating the rat sarcoma signaling protein, SOS1 (Son of sevenless homolog 1), in DCM pathogenesis.Methods:Exome sequencing was performed on 412 probands and family members from our

Background:Left ventricular ejection fraction (EF) is an indicator of cardiac function, usually assessed in individuals with heart failure and other cardiac conditions. Although family studies indicate that EF has an important genetic component with heritability estimates up to 0.61, to date only 6 EF-associated loci have been reported.Methods:Here, we conducted a genome-wide association study (GWAS)

Background:We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci.Methods:We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino)

Background:Genetic factors that influence kidney traits have been understudied for low-frequency and ancestry-specific variants.Methods:This study used imputed whole-genome sequencing from the Trans-Omics for Precision Medicine project to identify novel loci for estimated glomerular filtration rate and urine albumin-to-creatinine ratio in up to 12 207 Hispanics/Latinos. Replication was performed in

Background:The increase in serum triglyceride (TG) concentrations in response to a meal is considered a risk factor for cardiovascular disease. We aimed to elucidate the genetics of the postprandial TG response through genome-wide association studies (GWAS).Methods:Participants of the NEO (Netherlands Epidemiology of Obesity) study (n=5630) consumed a liquid mixed meal after an overnight fast. GWAS

Background:DNA methylation patterns associated with habitual diet have not been well studied.Methods:Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides)

Background:The discovery that much of the non–protein-coding genome is transcribed and plays a diverse functional role in fundamental cellular processes has led to an explosion in the development of tools and technologies to investigate the role of these noncoding RNAs in cardiovascular health. Furthermore, identifying noncoding RNAs for targeted therapeutics to treat cardiovascular disease is an emerging

Advances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases, including cardiomyopathies, arrhythmic disorders, vascular disorders, and lipid disorders such as familial hypercholesterolemia. However, not all cardiovascular practitioners are fully aware of the utility and potential pitfalls of incorporating genetic test results into the care of patients

Background:Increasing use of genetic tests have identified many variants of uncertain significance (VUS) in genes associated with inherited arrhythmias and cardiomyopathies. Evaluation of clinical practices, including medical management recommendations for VUS patients and their families, is important to prevent over- or under-treatment that may result in morbidity or mortality. The purpose of this

Background:While postoperative myocardial injury remains a major driver of morbidity and mortality, the ability to accurately identify patients at risk remains limited despite decades of clinical research. The role of genetic information in predicting myocardial injury after noncardiac surgery (MINS) remains unknown and requires large scale electronic health record and genomic data sets.Methods:In