作者
Themistocles Assimes, Catherine Tcheandjieu, Xiang Zhu, Austin Hilliard, Shoa Clarke, Valerio Napolioni, Shining Ma, Huaying Fang, Bryan R Gorman, Kyung Min Lee, Fei Chen, Saiju Pyarajan, Rebecca Song, Mary Plomondon, Thomas Maddox, Stephen Waldo, Nasa Sinnott-Armstrong, Yuk-Lam Ho, Genevieve Wojcik, Steven Buyske, Charles Kooperberg, Jeffrey Haessler, Ruth Loos, Ron Do, Marie Verbanck, Kumardeep Chaudhary, Kari North, Christy Avery, Christopher Haiman, Loic Le Marchand, Lynne Wilkens, Joshua Bis, Hampton Leonard, Botong Shen, Leslie Lange, Ayush Giri, Yingchang Lu, Ozan Dikilitas, Iftikhar Kullo, Ian Stanaway, Gail Jarvik, Adam Gordon, Scott Hebbring, Bahram Namjou, Kenneth Kaufman, Satoshi Koyama, Kaoru Ito, Kazuyoshi Ishigaki, Yoichiro Kamatani, Noah Tsao, Shefali Verma, Marylyn Ritchie, Rachel Kember, Aris Baras, Luca Lotta, Pradeep Natarajan, Michael Levin, Elizabeth Hauser, Donald Miller, Marijana Vujkovic, Jennifer Huffman, Sridharan Raghavan, Derek Klarin, Jennifer Lee, Benjamin Voight, Daniel Rader, Kyong-Mi Chang, Scott Damrauer, Julie Lynch, Peter Wilson, Hua Tang, Yan Sun, Phil Tsao, Christopher O'Donnell, Sekar Kathiresan, Danish Saleheen, J Michael Gaziano, Peter Reaven, Kelly Cho, Alexander Bick, Mariaelisa Graff, Jie Huang
发表日期
2021/3/10
简介
Abstract 122 Coronary artery disease (CAD) is a leading cause of death, yet its genetic determinants are not 123 fully elucidated. We report a multi-ethnic genome-wide association study of CAD involving 124 nearly a quarter of a million cases, incorporating the largest cohorts to date of Whites, Blacks, 125 and Hispanics from the Million Veteran Program with existing studies including 126 CARDIoGRAMplusC4D, UK Biobank, and Biobank Japan. We verify substantial and nearly 127 equivalent heritability of CAD across multiple ancestral groups, discover 107 novel loci 128 including the first nine on the X-chromosome, identify the first eight genome-wide significant 129 loci among Blacks and Hispanics, and demonstrate that two common haplotypes are largely 130 responsible for the risk stratification at the well-known 9p21 locus in most populations except 131 those of African origin where both haplotypes are virtually absent. We identify 15 loci for 132 angiographically derived burden of coronary atherosclerosis, which robustly overlap with the 133 strongest and earliest loci reported to date for clinical CAD. Phenome-wide association 134 analyses of novel loci and externally validated polygenic risk scores (PRS) augment signals 135 from the insulin resistance cluster of risk factors and consequences, extend previously 136 established pleiotropic associations of loci with traditional risk factors to include smoking and 137 family history, and confirm a substantially reduced transferability of existing PRS to Blacks. 138 Downstream integrative genomic analyses reinforce the critical role of endothelial, fibroblast, 139 and smooth muscle cells within the …
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T Assimes, C Tcheandjieu, X Zhu, A Hilliard, S Clarke… - 2021