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cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

Emelia Benjamin and colleagues report a meta-analysis of genome-wide association study data for atrial fibrillation, a condition associated with stroke and heart failure, in five European community-based cohorts of the CHARGE consortium. They report an association in ZFHX3 to atrial fibrillation, with replication in an independent cohort from the German AF Network.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Women with atrial fibrillation (AF) generally experience worse symptoms, poorer quality of life, and have higher risk of stroke and death than men with AF. In this Review, Ko et al. summarize the evidence on sex-specific differences in the utilization and outcomes of treatments for AF, including rate-control and rhythm-control strategies, and stroke-prevention therapy.

Genome-wide analyses identify variants associated with sinus node dysfunction, distal conduction disease and pacemaker implantation, implicating ion channel function, cardiac developmental programs and sarcomeric structure in bradyarrhythmia susceptibility.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

Differences between women and men with atrial fibrillation have received far less attention in recent years than sex-specific differences in coronary heart disease and stroke. In this Review, Ko et al. discuss sex-specific differences in the incidence, prevalence, risk factors, and pathophysiology of atrial fibrillation, and the clinical presentation and prognosis of patients with this prevalent arrhythmia.

On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Patrick Ellinor and colleagues report meta-analyses of common and rare variant association studies for atrial fibrillation across multiple populations. They identify 12 new loci, some of which implicate genes in atrial electrical and mechanical function.

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

Genome-wide association meta-analyses identify more than 350 loci associated with atrial fibrillation. A polygenic score derived from these results improves atrial fibrillation risk prediction compared to published clinical and polygenic scores.

A multi-ancestry meta-regression study analyses diverse genome-wide association studies and genome loci associated with tobacco and alcohol use.

A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.

Patrick Ellinor and colleagues report a meta-analysis of genome-wide association studies for atrial fibrillation in European populations. They identify six newly associated loci, four of which were replicated in a Japanese study.

A strategy for inferring phase for rare variant pairs is applied to exome sequencing data for 125,748 individuals from the Genome Aggregation Database (gnomAD). This resource will aid interpretation of rare co-occurring variants in the context of recessive disease.

The prevalence of atrial fibrillation (AF) is estimated to increase worldwide, mainly as a consequence of generalized population ageing. Even though the rise in AF prevalence is a global trend, data from Africa, Asia, and South America are limited and might underestimate the true frequency of AF. In this Review, the authors discuss the available epidemiological data on AF and highlight the widespread inadequacy of its treatment.

This large, multi-ethnic genome-wide association study identifies 97 loci significantly associated with atrial fibrillation. These loci are enriched for genes involved in cardiac development, electrophysiology, structure and contractile function.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

Analysis of whole-genome sequences of 25,465 individuals of European ancestry shows that rare variants contribute substantially to the heritability of height and body mass index.

Genome-wide analyses of cardiac magnetic resonance imaging data identify loci associated with right heart structure and function. A polygenic predictor of right ventricular ejection fraction is associated with dilated cardiomyopathy risk.

A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

Accurate classification of genetic variants is critical for research and patient care. Here, the authors report that population-based associations between rare variants and quantitative endophenotypes for monogenic diseases can provide support for variant pathogenicity.

Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.

A novel variant annotation metric that quantifies the level of expression of genetic variants across tissues is validated in the Genome Aggregation Database (gnomAD) and is shown to improve rare variant interpretation.

Genome-wide association analyses identify variants associated with thoracic aortic diameter. A polygenic score for ascending aortic diameter was associated with a diagnosis of thoracic aortic aneurysm in independent samples.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Abnormal PR interval duration is associated with risk for atrial fibrillation and heart block. Here, van Setten et al. identify 44 PR interval loci in a genome-wide association study of over 92,000 individuals and find genetic overlap with QRS duration, heart rate and atrial fibrillation.

Pooling participant-level genetic data into a single analysis can result in variance stratification, reducing statistical performance. Here, the authors develop variant-specific inflation factors to assess variance stratification and apply this to pooled individual-level data from whole genome sequencing.

Patrick Ellinor and colleagues report a genome-wide association study identifying variants in KCNN3 associated to lone atrial fibrillation.

Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.

Daniel Levy and colleagues report a meta-analysis of genome-wide association studies for blood pressure traits as part of the CHARGE consortium, reporting eight loci with replicated association to systolic and/or diastolic blood pressure, with one of these loci also associated to hypertension.

Arne Pfeufer and colleagues report a genome-wide association study of the electrocardiographic measurement of PR interval in seven population-based cohorts in the CHARGE consortium. They identify nine loci associated with PR interval and highlight candidate genes with a role in ion channels and cardiac development.

STAAR is a powerful rare variant association test that incorporates variant functional categories and complementary functional annotations using a dynamic weighting scheme based on annotation principal components. STAAR accounts for population structure and relatedness and is scalable for analyzing large whole-genome sequencing studies.

The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

Common genetic variants associated with plasma lipids have been extensively studied for a better understanding of common diseases. Here, the authors use whole-genome sequencing of 16,324 individuals to analyze rare variant associations and to determine their monogenic and polygenic contribution to lipid traits.

The disparities amplified by the COVID-19 pandemic present disturbing evidence that we are far from cardiovascular health-care equity. Individuals, leaders and institutions must prioritize research, policies and structures to advance diversity, equity, inclusion and belonging — Diversity 4.0, a justice imperative, essential to advancing workforce excellence and cardiovascular health.

Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

The duration and frequency of episodes of atrial fibrillation (AF) and the longitudinal history of this arrhythmia can vary markedly across patients. The currently accepted scheme for AF classification is based on temporal rhythm-based patterns. In this Review, the authors discuss the advantages and limitations of this categorization, highlighting gaps in knowledge that are opportunities to re-examine the current scheme and may lead to future improvements in AF classification.

Analysis of predicted loss-of-function variants from 125,748 human exomes and 15,708 whole genomes in the Genome Aggregation Database (gnomAD) provides a roadmap for human ‘knockout’ studies and a guide for future research into disease biology and drug-target selection.