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PubMed · 39950338

Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.

Kruthika R Iyer·Shoa L Clarke·Rodrigo Guarischi-Sousa·Ketrin Gjoni·Adam S Heath·Erica P Young·Nathan O Stitziel·Cecelia Laurie·Jai G Broome·Alyna T Khan·Joshua P Lewis·Huichun Xu·May E Montasser·Kellan E Ashley·Natalie R Hasbani·Eric Boerwinkle·Alanna C Morrison·Nathalie Chami·Ron Do·Ghislain Rocheleau·Donald M Lloyd-Jones·Rozenn N Lemaitre·Joshua C Bis·James S Floyd·Gregory L Kinney·Donald W Bowden·Nicholette D Palmer·Emelia J Benjamin·Matthew Nayor·Lisa R Yanek·Brian G Kral·Lewis C Becker·Sharon L R Kardia·Jennifer A Smith·Lawrence F Bielak·Arnita F Norwood·Yuan-I Min·April P Carson·Wendy S Post·Stephen S Rich·David Herrington·Xiuqing Guo·Kent D Taylor·JoAnn E Manson·Nora Franceschini·Katherine S Pollard·Braxton D Mitchell·Ruth J F Loos·Myriam Fornage·Lifang Hou·Bruce M Psaty·Kendra A Young·Elizabeth A Regan·Barry I Freedman·Ramachandran S Vasan·Daniel Levy·Rasika A Mathias·Patricia A Peyser·Laura M Raffield·Charles Kooperberg·Alex P Reiner·Jerome I Rotter·Goo Jun·Paul S de Vries·Themistocles L Assimes
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Abstract

BACKGROUND: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear. METHOD AND RESULTS: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program. Single variant tests were performed on 58 706 SVs in a study sample of 11 556 CAD cases and 42 907 controls. Additionally, aggregate tests using sliding windows were performed to examine rare SVs. One genome-wide significant association was identified for a common biallelic intergenic duplication on chromosome 6q21 (P=1.54E-09, odds ratio=1.34). The sliding window-based aggregate tests found 1 region on chromosome 17q25.3, overlapping USP36, to be significantly associated with coronary artery disease (P=1.03E-10). USP36 is highly expressed in arterial and adipose tissues while broadly affecting several cardiometabolic traits. CONCLUSIONS: Our results suggest that SVs, both common and rare, may influence the risk of coronary artery disease.

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HumansCoronary Artery DiseaseGenome-Wide Association StudyMaleFemaleGenetic Predisposition to DiseaseMiddle AgedAgedPolymorphism, Single NucleotideCase-Control StudiesGenomic Structural VariationWhole Genome SequencingChromosomes, Human, Pair 6PhenotypeRisk Factorsassociation testingcoronary artery diseasegeneticsstructural variantswhole‐genome sequencingJournal ArticleResearch Support, N.I.H., Extramural

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Kruthika R Iyer, Shoa L Clarke, Rodrigo Guarischi-Sousa, Ketrin Gjoni, Adam S Heath, Erica P Young, Nathan O Stitziel, Cecelia Laurie, Jai G Broome, Alyna T Khan, Joshua P Lewis, Huichun Xu, May E Montasser, Kellan E Ashley, Natalie R Hasbani, Eric Boerwinkle, Alanna C Morrison, Nathalie Chami, Ron Do, Ghislain Rocheleau, Donald M Lloyd-Jones, Rozenn N Lemaitre, Joshua C Bis, James S Floyd, Gregory L Kinney, Donald W Bowden, Nicholette D Palmer, Emelia J Benjamin, Matthew Nayor, Lisa R Yanek, Brian G Kral, Lewis C Becker, Sharon L R Kardia, Jennifer A Smith, Lawrence F Bielak, Arnita F Norwood, Yuan-I Min, April P Carson, Wendy S Post, Stephen S Rich, David Herrington, Xiuqing Guo, Kent D Taylor, JoAnn E Manson, Nora Franceschini, Katherine S Pollard, Braxton D Mitchell, Ruth J F Loos, Myriam Fornage, Lifang Hou, Bruce M Psaty, Kendra A Young, Elizabeth A Regan, Barry I Freedman, Ramachandran S Vasan, Daniel Levy, Rasika A Mathias, Patricia A Peyser, Laura M Raffield, Charles Kooperberg, Alex P Reiner, Jerome I Rotter, Goo Jun, Paul S de Vries, Themistocles L Assimes. 2025-02-14. Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.. https://doi.org/10.1161/jaha.124.036499

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