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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1679-1692 |
| Number of pages | 14 |
| Journal | Nature Medicine |
| Volume | 28 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2022 |
Funding
This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by Veterans Administration awards I01-01BX003362, I01-BX004821 (K.-M.C., P.S.T.), I01-BX003340 (K.Cho, P.W.F.W.) and VA HSR RES 13-457 (VA Informatics and Computing Infrastructure). The content of this manuscript does not represent the views of the Department of Veterans Affairs or the United States Government. The eMERGE Network was initiated and funded by the National Human Genome Research Institute (NHGRI) through the following grants: Phase III: U01HG8657 (Kaiser Permanente Washington/University of Washington); U01HG8685 (Brigham and Women’s Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children’s Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Health Sciences); U01HG8684 (Children’s Hospital of Philadelphia); U01HG8673 (Northwestern University); U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG8676 (Partners Healthcare/Broad Institute); and U01HG8664 (Baylor College of Medicine); Phase II: U01HG006828 (Cincinnati Children’s Hospital Medical Center/Boston Children’s Hospital); U01HG006830 (Children’s Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health Cooperative/University of Washington); U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center); and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center). Phase II: U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers. Phase I: U01-HG-004610 (Group Health Cooperative/University of Washington); U01-HG-004608 (Marshfield Clinic Research Foundation and Vanderbilt University Medical Center); U01-HG-04599 (Mayo Clinic); U01HG004609 (Northwestern University); U01-HG-04603 (Vanderbilt University Medical Center, also serving as the Administrative Coordinating Center); U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers. The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the NHGRI with co-funding from the National Institute on Minority Health and Health Disparities (NIMHD), supported by U01HG007416 (CALiCo), U01HG007417 (ISMMS), U01HG007397 (MEC), U01HG007376 (WHI), and U01HG007419 (Coordinating Center). The MultiEthnic Study (MEC) was supported by U01 CA164973. The Women’s Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. Scientific Computing Infrastructure at Fred Hutch is funded by ORIP grant S10OD028685. Funding support for the ‘Exonic variants and their relation to complex traits in minorities of the WHI study is provided through the NHGRI PAGE program (U01HG004790). The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C). The Cardiovascular Health Study (CHS) was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006; and NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393 and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. BioBank Japan (BBJ) was supported by the Tailor-Made Medical Treatment Program of the Ministry of Education, Culture, Sports, Science, and Technology and Japan Agency for Medical Research (AMED) under grant numbers JP17km0305002 and JP17km0305001. Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) was funded by the Interlaboratory Proposal Funding of the Intramural Research Program of the National Institute on Aging (NIA), the National Institutes of Health (NIH), Baltimore, Maryland. Funding number: [AG000989]. X.Z. was supported by the Stein Fellowship from Stanford University and Institute for Computational and Data Sciences Seed Grant from The Pennsylvania State University. S.M.D., J.A.L. and K.M.L. were supported by the US Department of Veterans Affairs (IK2-CX001780). Y.L. is supported by NIH R56HL150186. S.Ko. and K.It. were supported by AMED under Grant Numbers JP20km0405209 and JP20ek0109487. K.E.N. is supported by NIH R01HL142302. R.D. is supported by NIH R35GM124836 and R01HL139865. F.C. is supported by NCI T32CA229110. B.F.V. was supported by the NIH R01DK101478 and a Linda Pechenik Montague Investigator Award. P.N. is supported by grants from the NIH/NHLBI (R01HL142711, R01HL148050, R01HL127564, R01HL151152), NIH/NHGRI (U01HG011719), Fondation Leducq (TNE-18CVD04) and Massachusetts General Hospital (Fireman Chair). Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. The authors thank C. D. Bustamante for his review and feedback of specific cross-population analyses involving the 9p21 region. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A.B. and L.A.Lo. are employees of Regeneron Pharmaceuticals. R.D. has received grants from AstraZeneca, grants and non-financial support from Goldfinch Bio, is a scientific co-founder, consultant and equity holder for Pensieve Health and a consultant for Variant Bio. T.M.M. is an employee of the Healthcare Innovation Lab at BJC HealthCare/Washington University School of Medicine, an advisor of Myia Labs, and a compensated director of the JF Maddox Foundation in New Mexico. S.Ka. is an employee of Verve Therapeutics, holds equity in Verve Therapeutics and Maze Therapeutics, and has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Color Genomics, MedGenome, Quest and Medscape. D.J.R. is on the Scientific Advisory Board of Alnylam, Novartis and Verve Therapeutics. M.D.R. is on the scientific advisory board for Goldfinch Bio and Cipherome. C.J.O. became an employee of Novartis after the initial submission of the manuscript. P.N. reports investigator-initiated grants from Amgen, Apple, AstraZeneca, Boston Scientific and Novartis, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Invitae, Foresite Labs, Novartis and Roche/Genentech, and is a co-founder of TenSixteen Bio, a shareholder of geneXwell, TenSixteen Bio and Vertex, a scientific advisory board member of geneXwell and TenSixteen Bio, and reports spousal employment at Vertex, all unrelated to the present work. S.M.D. receives research support from RenalytixAI to his institution and consulting fees from Calico Labs. A.G.B. is a scientific co-founder and equity holder in TenSixteen Bio. All other authors have no competing interests. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by Veterans Administration awards I01-01BX003362, I01-BX004821 (K.-M.C., P.S.T.), I01-BX003340 (K.Cho, P.W.F.W.) and VA HSR RES 13-457 (VA Informatics and Computing Infrastructure). The content of this manuscript does not represent the views of the Department of Veterans Affairs or the United States Government. The eMERGE Network was initiated and funded by the National Human Genome Research Institute (NHGRI) through the following grants: Phase III: U01HG8657 (Kaiser Permanente Washington/University of Washington); U01HG8685 (Brigham and Women’s Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children’s Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Health Sciences); U01HG8684 (Children’s Hospital of Philadelphia); U01HG8673 (Northwestern University); U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG8676 (Partners Healthcare/Broad Institute); and U01HG8664 (Baylor College of Medicine); Phase II: U01HG006828 (Cincinnati Children’s Hospital Medical Center/Boston Children’s Hospital); U01HG006830 (Children’s Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health Cooperative/University of Washington); U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center); and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center). Phase II: U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers. Phase I: U01-HG-004610 (Group Health Cooperative/University of Washington); U01-HG-004608 (Marshfield Clinic Research Foundation and Vanderbilt University Medical Center); U01-HG-04599 (Mayo Clinic); U01HG004609 (Northwestern University); U01-HG-04603 (Vanderbilt University Medical Center, also serving as the Administrative Coordinating Center); U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers. The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the NHGRI with co-funding from the National Institute on Minority Health and Health Disparities (NIMHD), supported by U01HG007416 (CALiCo), U01HG007417 (ISMMS), U01HG007397 (MEC), U01HG007376 (WHI), and U01HG007419 (Coordinating Center). The MultiEthnic Study (MEC) was supported by U01 CA164973. The Women’s Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. Scientific Computing Infrastructure at Fred Hutch is funded by ORIP grant S10OD028685. Funding support for the ‘Exonic variants and their relation to complex traits in minorities of the WHI study is provided through the NHGRI PAGE program (U01HG004790). The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C). The Cardiovascular Health Study (CHS) was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006; and NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393 and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. BioBank Japan (BBJ) was supported by the Tailor-Made Medical Treatment Program of the Ministry of Education, Culture, Sports, Science, and Technology and Japan Agency for Medical Research (AMED) under grant numbers JP17km0305002 and JP17km0305001. Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) was funded by the Interlaboratory Proposal Funding of the Intramural Research Program of the National Institute on Aging (NIA), the National Institutes of Health (NIH), Baltimore, Maryland. Funding number: [AG000989]. X.Z. was supported by the Stein Fellowship from Stanford University and Institute for Computational and Data Sciences Seed Grant from The Pennsylvania State University. S.M.D., J.A.L. and K.M.L. were supported by the US Department of Veterans Affairs (IK2-CX001780). Y.L. is supported by NIH R56HL150186. S.Ko. and K.It. were supported by AMED under Grant Numbers JP20km0405209 and JP20ek0109487. K.E.N. is supported by NIH R01HL142302. R.D. is supported by NIH R35GM124836 and R01HL139865. F.C. is supported by NCI T32CA229110. B.F.V. was supported by the NIH R01DK101478 and a Linda Pechenik Montague Investigator Award. P.N. is supported by grants from the NIH/NHLBI (R01HL142711, R01HL148050, R01HL127564, R01HL151152), NIH/NHGRI (U01HG011719), Fondation Leducq (TNE-18CVD04) and Massachusetts General Hospital (Fireman Chair). Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. The authors thank C. D. Bustamante for his review and feedback of specific cross-population analyses involving the 9p21 region. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology