Rare variant contribution to the heritability of coronary artery disease
Ghislain Rocheleau, Shoa L. Clarke, Gaëlle Auguste, Natalie R. Hasbani, Alanna C. Morrison, Adam S. Heath, Lawrence F. Bielak, Kruthika Iyer, Erica P. Young, Nathan O. Stitziel, Goo Jun, Cecelia 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 Kooperberg, Brian G. Kral, Ruth J. F. Loos, Sharon M. Lutz, JoAnn E. Manson, Lisa W. Martin, Braxton D. Mitchell, Rami Nassir, Nicholette D. Palmer, Wendy S. Post, Michael 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 L. 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 L. DeMeo, Paul S. de Vries, Qing Duan, Charles B. Eaton, Lynette Ekunwe, Adel Boueiz, Shanshan Gao, Yan Gao, Margery Gass, Auyon Ghosh, Daniel Grine, Michael E. Hall, Craig P. Hersh, Brian D. Hobbs, Chao A. Hsiung, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Rebecca D. Jackson, Jill M. Johnsen, Christoph Lange, Ethan M. Lange, Meryl S. LeBoff, Wen‐Jane Lee, Yun Li, Simin Liu, Yu Liu, Susan Mathai, Hao Mei, Rakhi P. Naik, Take Naseri, Bonnie Neltner, Heather M. Ochs‐Balcom, David T. Paik, Cora Parker, Marco Perez, Ulrike Peters, Lawrence S. Phillips, Julia Powers Becker
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. 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 genetic risk.