Rare variant contribution to the heritability of coronary artery disease

作者：Ghislain Rocheleau, Shoa L. Clarke, Gaelle E Auguste, Natalie R. Hasbani, Alanna C. Morrison, Adam S. Heath, Lawrence F. Bielak, Kruthika Raman Iyer, Erica P. Young, Nathan O. Stitziel, Goo Jia Jun, Cecelia A. Laurie, Jai Broome, Alyna Khan, Donna K. Arnett, Lewis C. Becker, Joshua C. Bis, Eric Boerwinkle, Donald W. Bowden, April P. Carson, Patrick T. Ellinor, Myriam Fornage, Nora Franceschini, Barry I. Freedman, Nancy L. Heard‐Costa, Lifang Hou, Yii‐Der Ida Chen, Eimear E. Kenny, Charles L Kooperberg, Brian G. Kral, Ruth J. F. Loos, Sharon Marie Lutz, JoAnn E. Manson, Lisa Warsinger Martin, Braxton D. Mitchell, Rami Nassir, Nicholette D. Palmer, Wendy S. Post, Michael H Preuss, Bruce M. Psaty, Laura M. Raffield, Elizabeth A. Regan, Stephen S. Rich, Jennifer A. Smith, Kent D. Taylor, Lisa R. Yanek, Kendra A. Young, Pramod Anugu, Paul Livermore Auer, Lucas Barwick, Diane M. Becker, Cara L. Carty, Peter J. Castaldi, Mark Chaffin, Yi‐Cheng Chang, Seung Hoan Choi, Ren-Hua Chung, Carolyn Crandall, Sean David, Lisa de las Fuentes, Ranjan Deka, Dawn Lisa DeMeo, Paul S. de Vries, Qing Duan, Charles B. Eaton, Lynette Ekunwe, Adel Boueiz, Shanshan Gao, Yan Ming Gao, Margery Gass, Auyon Ghosh, Daniel Grine, Michael E. Hall, Craig P. Hersh, Brian D. Hobbs, Chao Agnes Hsiung, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Rebecca D. Jackson, Jill M. Johnsen, Christoph Lange, Ethan M. Lange, Meryl Susan LeBoff, Wen‐Jane Lee, Yun Li, Simin Liu, Yu Liu, Susan K. Mathai, Hao Mei, Rakhi P P. Naik, Take Naseri, Bonnie S. Neltner, Heather M. Ochs‐Balcom, David T. Paik, Cora Parker, Marco Perez, Ulrike Peters, Lawrence S. Phillips, Julia Powers Becker, Muagututi‘a Sefuiva Reupena, Carolina Roselli, Pamela H. Russell, Éster Cerdeira Sabino, Kevin Sandow, Karen Schwander, Frank C. Sciurba, Brian Silver, Sylvia Smoller, Beverly M. Snively, Garrett Storm, Yun Ju Sung, Hua Tang, Margaret A. Taub, Lesley Tinker, David Tirschwell, Hemant K. Tiwari, Dhananjay M. Vaidya, Tarik Walker, Robert B. Wallace, Avram D. Walts, Lu-Chen Weng, Ivana V. Yang, Snow Xueyan Zhao, Austin T. Hilliard, Catherine Tcheandjieu, Patricia A. Peyser, Ramachandran Srini Vasan, Jerome I. Rotter, Clint L. Miller, Themistocles L. Assimes, Paul S. de Vries, Ron Do · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-52939-6 · 被引用次数：20 · 研究领域：Cardiovascular Function and Risk Factors、Genetic Associations and Epidemiology、Lipid metabolism and disorders

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. Whole genome sequences enable discovery of rare variants which may help to explain the heritability of common diseases. Here the authors find that ultra-rare variants explain ~50% of coronary artery disease (CAD) heritability and highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD g...