Large-scale genome-wide association study of coronary artery disease in genetically diverse populations – PubMed

doi: 10.1038/s41591-022-01891-3. Online ahead of print.
Catherine Tcheandjieu #  1   2   3   4 Xiang Zhu #  5   6   7   8 Austin T Hilliard #  5 Shoa L Clarke #  5   9 Valerio Napolioni  10   11 Shining Ma  6 Kyung Min Lee  12 Huaying Fang  13 Fei Chen  14 Yingchang Lu  15 Noah L Tsao  16 Sridharan Raghavan  17   18 Satoshi Koyama  19 Bryan R Gorman  20   21 Marijana Vujkovic  22   23 Derek Klarin  5   20   24   25   26   27 Michael G Levin  22   23 Nasa Sinnott-Armstrong  5   13 Genevieve L Wojcik  28 Mary E Plomondon  29   30 Thomas M Maddox  31   32 Stephen W Waldo  29   30   33 Alexander G Bick  34 Saiju Pyarajan  20   35 Jie Huang  20   36   37 Rebecca Song  20 Yuk-Lam Ho  20 Steven Buyske  38 Charles Kooperberg  39 Jeffrey Haessler  39 Ruth J F Loos  40 Ron Do  40   41 Marie Verbanck  40   41   42 Kumardeep Chaudhary  40   41 Kari E North  43 Christy L Avery  43 Mariaelisa Graff  43 Christopher A Haiman  14 Loïc Le Marchand  44 Lynne R Wilkens  44 Joshua C Bis  45 Hampton Leonard  46   47 Botong Shen  48 Leslie A Lange  49   50   51 Ayush Giri  52   53 Ozan Dikilitas  54 Iftikhar J Kullo  54 Ian B Stanaway  55 Gail P Jarvik  56   57 Adam S Gordon  58 Scott Hebbring  59 Bahram Namjou  60   61 Kenneth M Kaufman  60 Kaoru Ito  19 Kazuyoshi Ishigaki  62 Yoichiro Kamatani  62   63 Shefali S Verma  64   65 Marylyn D Ritchie  64   65 Rachel L Kember  22   66 Aris Baras  67 Luca A Lotta  67 Regeneron Genetics CenterCARDIoGRAMplusC4D ConsortiumBiobank JapanMillion Veteran ProgramSekar Kathiresan  25   68   69   70 Elizabeth R Hauser  71   72 Donald R Miller  73   74 Jennifer S Lee  5   75 Danish Saleheen  22   76 Peter D Reaven  77   78 Kelly Cho  20   35 J Michael Gaziano  20   35 Pradeep Natarajan  25   69   79 Jennifer E Huffman  20 Benjamin F Voight  22   64   80   81 Daniel J Rader  23 Kyong-Mi Chang  22   23 Julie A Lynch  82   83 Scott M Damrauer  16   22   64 Peter W F Wilson  84   85 Hua Tang  13 Yan V Sun  86   87 Philip S Tsao  5   75   88 Christopher J O'Donnell  20   35 Themistocles L Assimes  89   90   91   92

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Catherine Tcheandjieu et al. Nat Med. .

Abstract

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

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#Largescale #genomewide #association #study #coronary #artery #disease #genetically #diverse #populations #PubMed

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