@article{5a584a9e01c94971b812a8f8f7e3b86b,
title = "Rare variant contribution to the heritability of coronary artery disease",
abstract = "Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.",
author = "{NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and Ghislain Rocheleau and Clarke, {Shoa L.} and Ga{\"e}lle Auguste and Hasbani, {Natalie R.} and Morrison, {Alanna C.} and Heath, {Adam S.} and Bielak, {Lawrence F.} and Iyer, {Kruthika R.} and Young, {Erica P.} and Stitziel, {Nathan O.} and Goo Jun and Cecelia Laurie and Broome, {Jai G.} and Khan, {Alyna T.} and Arnett, {Donna K.} and Becker, {Lewis C.} and Bis, {Joshua C.} and Eric Boerwinkle and Bowden, {Donald W.} and Carson, {April P.} and Ellinor, {Patrick T.} and Myriam Fornage and Nora Franceschini and Freedman, {Barry I.} and Heard-Costa, {Nancy L.} and Lifang Hou and Chen, {Yii Der Ida} and Kenny, {Eimear E.} and Charles Kooperberg and Kral, {Brian G.} and Loos, {Ruth J.F.} and Lutz, {Sharon M.} and Manson, {Jo Ann E.} and Martin, {Lisa W.} and Mitchell, {Braxton D.} and Rami Nassir and Palmer, {Nicholette D.} and Post, {Wendy S.} and Preuss, {Michael H.} and Psaty, {Bruce M.} and Raffield, {Laura M.} and Regan, {Elizabeth A.} and Rich, {Stephen S.} and Smith, {Jennifer A.} and Taylor, {Kent D.} and Yanek, {Lisa R.} and Young, {Kendra A.} and Zhao, {Snow Xueyan} and Ivana Yang and Weng, {Lu Chen} and Avram Walts and Robert Wallace and Tarik Walker and Dhananjay Vaidya and Hemant Tiwari and David Tirschwell and Lesley Tinker and Margaret Taub and Hua Tang and Sung, {Yun Ju} and Garrett Storm and Beverly Snively and Sylvia Smoller and Brian Silver and Frank Sciurba and Karen Schwander and Kevin Sandow and Sabino, {Ester Cerdeira} and Pamela Russell and Carolina Roselli and Reupena, {Muagututi{\textquoteright}a Sefulva} and Becker, {Julia Powers} and Phillips, {Lawrence S.} and Ulrike Peters and Marco Perez and Cora Parker and Paik, {David T.} and Heather Ochs-Balcom and Bonnie Neltner and Take Naseri and Rakhi Naik and Hao Mei and Susan Mathai and Yu Liu and Simin Liu and Yun Li and Lee, {Wen Jane} and Meryl LeBoff and Ethan Lange and Christoph Lange and Jill Johnsen and Rebecca Jackson and Hwu, {Chii Min} and Haley Huston and Hung, {Yi Jen} and Hsiung, {Chao Agnes} and Brian Hobbs and Craig Hersh and Michael Hall and Daniel Grine and Auyon Ghosh and Margery Gass and Yan Gao and Shanshan Gao and {El Boueiz}, Adel and Lynette Ekunwe and Charles Eaton and Qing Duan and {de Vries}, {Paul S.} and Dawn DeMeo and Ranjan Deka and {de las Fuentes}, Lisa and Sean David and Carolyn Crandall and Chung, {Ren Hua} and Choi, {Seung Hoan} and Chang, {Yi Cheng} and Mark Chaffin and Peter Castaldi and Cara Carty and Diane Becker and Lucas Barwick and Paul Auer and Pramod Anugu and Hilliard, {Austin T.} and Catherine Tcheandjieu and Peyser, {Patricia A.} and Vasan, {Ramachandran S.} and Rotter, {Jerome I.} and Miller, {Clint L.} and Assimes, {Themistocles L.} and {de Vries}, {Paul S.} and Ron Do",
note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",
year = "2024",
month = dec,
doi = "10.1038/s41467-024-52939-6",
language = "English",
volume = "15",
journal = "Nature communications",
issn = "2041-1723",
number = "1",
}