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Pradeep Natarajan, Email: pnatarajan@mgh.harvard.edu
K.C. and P.N. conceived of the study, with input from D.C., S.J., J.M., A.A.B., D.K., E.W., and C. L, and supervised all analyses. J.Brody, J.Bressler, N.S., M.F, V.C., R.A.G., J.R., E.B., J.F., B.P., and C.M.B. collected, pre-processed, and provided expertise on the data analyzed in this study. P.N., A.G.B., T.N., J.W., D.N., M.H., R.B., and G.G. performed the calling of CHIP in all samples, with input and supervision from B.E. and S.J. M.U. performed the discovery, enrichment, and MR analyses, with input from A.P. and T.N. B.Y. and N.N. performed the replication analyses, and K.C. carried out additional enrichment and functional annotation analyses. M.U. drafted the manuscript with critical input from P.N. and K.C. All authors read, contributed to, and approved the final manuscript.
We gratefully acknowledge funding from the National Institute on Aging (NIA: U34AG051418 to K.N.C., J.M., and A.A.B., R01AG059727 to C.L., T32AG047126, which supported D.N.), the National Institute of Environmental Health Sciences (NIEHS: P30ES009089 to A.A.B.), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS: R01AR041398 to D.K.), the National Heart Lung and Blood Institute (NHLBI: DP2-HL157540, to S.J., R01HL148050 to C.B., R01HL141989 to N.S.), and the American Heart Association (940166, 979465, to M.C.H.). P.N. is supported by grants from the NHLBI (R01HL142711, R01HL127564, R01HL148050, R01HL151283, R01HL148565, R01HL135242, R01HL151152), National Institute of Diabetes and Digestive and Kidney Diseases (R01DK125782), Fondation Leducq (TNE-18CVD04), and Massachusetts General Hospital (Paul and Phyllis Fireman Endowed Chair in Vascular Medicine). A.G.B. is supported by NIH grant DP5 OD029586, a Burroughs Wellcome Fund Career Award for Medical Scientists, and a Pew-Stewart Scholar for Cancer Research Award, supported by The Pew Charitable Trusts and the Alexander and Margaret Stewart Trust. R.B. is supported by the John S. LaDue Fellowship in Cardiovascular Disease Research. J.R. is 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 (NIDDK) Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center, as well as the NIDDK contract R01HL146860. Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01HL105756. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006; and NHLBI grants U01HL080295, R01HL087652, R01HL103612, R01HL120393, K08HL116640, R01HL092111, R01HL111089, R01HL116747 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). Merck Foundation/Society of Epidemiologic Research as well as Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. 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 UL1TR000124, 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. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, HHSN268201700005I). Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). CHARGE sequencing was carried out at the Baylor College of Medicine Human Genome Sequencing Center (U54 HG003273 and R01HL086694). Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO) and exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). Funding was also supported by 5RC2HL102419 and R01NS087541. The authors thank the staff and participants of the ARIC study for their important contributions. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. P.N. reports grant support from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, spousal employment and equity at Vertex, consulting income from Apple, AstraZeneca, Novartis, Genentech / Roche, Blackstone Life Sciences, Foresite Labs, and TenSixteen Bio, and is a scientific advisor board member and shareholder of TenSixteen Bio and geneXwell, all unrelated to this work. J.S.F. has consulted for Shionogi Inc. R.B has consulted for Casana Care Inc, unrelated to this work. J.M. has guest-lectured at Merck, unrelated to this work. M.C.H. has consulted for CRISPR Therapeutics and served on the advisory board for Miga Health, both unrelated to this work. D.K. serves on a DSMB for Agnovos Healthcare, a scientific advisory board for Pfizer and Solarea Bio, and reports grant support from Amgen and Solarea Bio. B.L.E. has received research funding from Celgene, Deerfield, Novartis, and Calico and consulting fees from GRAIL, and is a member of the scientific advisory board and shareholder for Neomorph Inc., TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics. S.J. and A.G.B. are co-founders and equity holders in TenSixteen Bio. The other authors declare no competing interests.
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