Key result
Whole-genome sequencing identifies 86 significant cardiovascular gene-phenotype associations, including 46 novel discoveries.
Why the study?
The effects of rare coding variants across cardiovascular disease groups are incompletely characterized, and the influence of functionally and clinically informed variant classification and sex-specific genetic effects on gene-phenotype associations remains understudied.
Do rare coding variants identified via functionally and clinically informed gene-burden testing associate with cardiovascular disease phenotypes across ancestries and sexes?
Cohort (n=483,311)
Yes
Do rare coding variants identified via functionally and clinically informed gene-burden testing associate with cardiovascular disease phenotypes across ancestries and sexes?
Large-scale whole-genome sequencing in 483,311 individuals reveals 46 novel cardiovascular gene-phenotype associations, highlighting roles for purinergic signaling, endothelial nitric oxide regulation, and sex-specific genetic effects.
Answers are grounded in this paper and cite their sources.
Novel associations remain hypothesis-generating; leaves open causal validation and clinical utility for risk prediction across ancestries.
Background: Rare coding variants contribute to cardiovascular disease, but their effects across disease groups remain incompletely characterized. In particular, the influence of functionally and clinically informed variant classification and sex-specific genetic effects on gene-phenotype associations remains understudied. Methods: We analyzed whole-genome sequencing data from up to 483,311 UK Biobank participants across six genetic ancestry groups and eight cardiovascular phenotype groups. Gene-burden testing integrated state-of-the-art missense classification and predicted pathogenic germline variants. We performed combined-sex and sex-stratified analyses, followed by cross-ancestry meta-analysis. We additionally adjusted for cardiometabolic traits in sensitivity analyses, estimated penetrance among qualifying-variant carriers, and assessed genetic prevalence across eight ancestry groups. Results: We identified 86 exome-wide significant gene-phenotype associations: 40 established and 46 novel. Novel associations included EHMT2 with atrial fibrillation, P2RX1 with arrhythmias, P2RY4 with complete atrioventricular block, and NOSTRIN with atherosclerotic heart disease in females. After cardiometabolic adjustment, 60 associations retained exome-wide significance and 18 additional associations emerged, including CDH11, PARVA, and ADAMDEC1 with atherosclerosis-related phenotypes. Conclusions: These findings identify novel cardiovascular gene-phenotype associations implicating purinergic signaling, endothelial nitric oxide regulation, and vascular wall biology. Variant selection shapes penetrance estimates and the interpretation of inherited susceptibility.
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Özçelık et al. (2026) conducted a cohort in Cardiovascular diseases across eight phenotype groups (n=483,311). Rare coding variants (missense and predicted pathogenic germline variants) vs. Non-carriers of qualifying variants was evaluated on Exome-wide significant gene-phenotype associations across eight cardiovascular phenotype groups. Whole-genome sequencing analysis of 483,311 participants identified 86 exome-wide significant cardiovascular gene-phenotype associations (40 established, 46 novel).
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