@article{cc9019aea6854f02a6a5d2284e06a6dd,
title = "Whole genome sequence analysis of blood lipid levels in >66,000 individuals",
abstract = "Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.",
author = "{NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and Selvaraj, {Margaret Sunitha} and Xihao Li and Zilin Li and Akhil Pampana and Zhang, {David Y.} and Joseph Park and Stella Aslibekyan and Bis, {Joshua C.} and Brody, {Jennifer A.} and Cade, {Brian E.} and Chuang, {Lee Ming} and Chung, {Ren Hua} and Curran, {Joanne E.} and {de las Fuentes}, Lisa and {de Vries}, {Paul S.} and Ravindranath Duggirala and Freedman, {Barry I.} and Mariaelisa Graff and Xiuqing Guo and Nancy Heard-Costa and Bertha Hidalgo and Hwu, {Chii Min} and Irvin, {Marguerite R.} and Kelly, {Tanika N.} and Kral, {Brian G.} and Leslie Lange and Xiaohui Li and Martin Lisa and Lubitz, {Steven A.} and Manichaikul, {Ani W.} and Preuss Michael and Montasser, {May E.} and Morrison, {Alanna C.} and Take Naseri and O{\textquoteright}Connell, {Jeffrey R.} and Palmer, {Nicholette D.} and Peyser, {Patricia A.} and Reupena, {Muagututia S.} and Smith, {Jennifer A.} and Xiao Sun and Taylor, {Kent D.} and Tracy, {Russell P.} and Tsai, {Michael Y.} and Zhe Wang and Yuxuan Wang and Wei Bao and Wilkins, {John T.} and Yanek, {Lisa R.} and Wei Zhao and Kaplan, {Robert C.}",
note = "Funding Information: Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). P.N. is supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL148050, R01HL151283, R01HL148565, R01HL135242, R01HL151152), Fondation Leducq (TNE-18CVD04), and Massachusetts General Hospital (Paul and Phyllis Fireman Endowed Chair in Vascular Medicine). G.M.P. is supported by NIH grants R01HL142711 and R01HL127564. X.Lin is supported by grants R35-CA197449, U19-CA203654, R01-HL113338, and U01-HG009088. Prior to his employment at Novartis and during this work S.A.L. was supported by NIH grants R01HL139731, R01HL157635, and American Heart Association 18SFRN34250007. We like to acknowledge all the grants that supported this study, R01 HL121007, U01 HL072515, R01 AG18728, X01HL134588, HL 046389, HL113338, and 1R35HL135818, K01 HL135405, R03 HL154284, U01HL072507, R01HL087263, R01HL090682, P01HL045522, R01MH078143, R01MH078111, R01MH083824, U01DK085524, R01HL113323, R01HL093093, R01HL140570, R01HL142711, R01HL127564, R01HL148050, R01HL148565, HL105756, and Leducq TNE-18CVD04. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S.Department of Health and Human Services. Detailed acknowledgements provided in Supplementary Note 2. Funding Information: Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). P.N. is supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL148050, R01HL151283, R01HL148565, R01HL135242, R01HL151152), Fondation Leducq (TNE-18CVD04), and Massachusetts General Hospital (Paul and Phyllis Fireman Endowed Chair in Vascular Medicine). G.M.P. is supported by NIH grants R01HL142711 and R01HL127564. X.Lin is supported by grants R35-CA197449, U19-CA203654, R01-HL113338, and U01-HG009088. Prior to his employment at Novartis and during this work S.A.L. was supported by NIH grants R01HL139731, R01HL157635, and American Heart Association 18SFRN34250007. We like to acknowledge all the grants that supported this study, R01 HL121007, U01 HL072515, R01 AG18728, X01HL134588, HL 046389, HL113338, and 1R35HL135818, K01 HL135405, R03 HL154284, U01HL072507, R01HL087263, R01HL090682, P01HL045522, R01MH078143, R01MH078111, R01MH083824, U01DK085524, R01HL113323, R01HL093093, R01HL140570, R01HL142711, R01HL127564, R01HL148050, R01HL148565, HL105756, and Leducq TNE-18CVD04. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S.Department of Health and Human Services. Detailed acknowledgements provided in Supplementary Note . Funding Information: P.N. reports investigator-initiated grant support from Amgen, Apple, AstraZeneca, and Boston Scientific, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech, TenSixteen Bio, and Novartis, scientific advisory board membership of geneXwell and TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. B.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. M.E.M. receives funding from Regeneron Pharmaceutical Inc. unrelated to this work. S.A. has employment and equity in 23andMe, Inc. The spouse of C.J.W. works at Regeneron. S.A.L. is a full-time employee of Novartis as of July 18, 2022. S.A.L. has received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier, and IBM, and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences, and Invitae. X. Lin is a consultant of AbbVie Pharmaceuticals and Verily Life Sciences. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-33510-7",
language = "English (US)",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}