Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program

被引：38

作者：

Verma, Anurag ^{[1
,2
,3
]}

Huffman, Jennifer E. ^{[4
,5
,6
]}

Rodriguez, Alex ^{[7
]}

Conery, Mitchell ^{[8
]}

Liu, Molei ^{[9
]}

Ho, Yuk-Lam ^{[4
]}

Kim, Youngdae ^{[10
]}

Heise, David A. ^{[11
]}

Guare, Lindsay ^{[2
]}

Panickan, Vidul Ayakulangara ^{[12
]}

Garcon, Helene ^{[4
]}

Linares, Franciel ^{[13
]}

Costa, Lauren ^{[14
]}

Goethert, Ian ^{[15
]}

Tipton, Ryan ^{[16
]}

Honerlaw, Jacqueline ^{[4
]}

Davies, Laura ^{[17
]}

Whitbourne, Stacey ^{[6
,14
,18
]}

Cohen, Jeremy ^{[11
]}

Posner, Daniel C. ^{[4
]}

Sangar, Rahul ^{[14
]}

Murray, Michael ^{[14
]}

Wang, Xuan ^{[12
,19
]}

Dochtermann, Daniel R. ^{[20
]}

Devineni, Poornima ^{[20
]}

Shi, Yunling ^{[20
]}

Nandi, Tarak Nath ^{[7
]}

Assimes, Themistocles L. ^{[21
]}

Brunette, Charles A. ^{[6
,22
]}

Carroll, Robert J. ^{[23
]}

Clifford, Royce ^{[24
,25
]}

Duvall, Scott ^{[26
,27
]}

Gelernter, Joel ^{[28
,29
]}

Hung, Adriana ^{[30
,31
]}

Iyengar, Sudha K. ^{[32
,33
,34
,35
]}

Joseph, Jacob ^{[36
,37
]}

Kember, Rachel ^{[38
,39
]}

Kranzler, Henry ^{[38
,39
]}

Kripke, Colleen M. ^{[2
]}

Levey, Daniel ^{[28
,40
]}

Luoh, Shiuh-Wen ^{[41
,42
]}

Merritt, Victoria C. ^{[24
]}

Overstreet, Cassie ^{[28
]}

Deak, Joseph D. ^{[43
,44
]}

Grant, Struan F. A. ^{[45
,46
,47
,48
]}

Polimanti, Renato ^{[43
]}

Roussos, Panos ^{[49
,50
]}

Shakt, Gabrielle ^{[1
,51
]}

Sun, Yan V. ^{[52
]}

Tsao, Noah ^{[1
,51
]}

机构：

[1] Corporal Michael Crescenz VA Med Ctr, Philadelphia, PA 19104 USA

[2] Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA

[3] Univ Penn, Inst Biomed Informat, Perelman Sch Med, Philadelphia, PA 19104 USA

[4] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MAV, Boston, MA 02130 USA

[5] Palo Alto Hlth Care Syst, Palo Alto Vet Inst Res PAVIR, Palo Alto, CA 94304 USA

[6] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[7] Argonne Natl Lab, Data Sci & Learning, Lemont, IL 60439 USA

[8] Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA

[9] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY 10032 USA

[10] Argonne Natl Lab, Math & Comp Sci Div, Lemont, IL 60439 USA

[11] Oak Ridge Natl Lab, Dept Energy, Cyber Resilience & Intelligence Div, Natl Secur Sci Directorate, Oak Ridge, TN 37831 USA

[12] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA

[13] Oak Ridge Natl Lab, Dept Energy, Informat Technol Serv Directorate, R&D Syst Engn, Oak Ridge, TN 37831 USA

[14] VA Boston Healthcare Syst, MVP Boston Coordinating Ctr, Boston, MA 02111 USA

[15] Oak Ridge Natl Lab, Dept Energy, Informat Technol Serv Div, Data Management & Engn, Oak Ridge, TN 37831 USA

[16] Oak Ridge Natl Lab, Dept Energy, Informat Technol Serv Div, Knowledge Discovery Infrastruct, Oak Ridge, TN 37831 USA

[17] Oak Ridge Natl Lab, Dept Energy, Comp & Computat Sci Dir PMO, PMO, Oak Ridge, TN 37831 USA

[18] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA

[19] Univ Utah, Dept Populat Hlth Sci, Salt Lake City, UT 84112 USA

[20] VA Boston Healthcare Syst, VA Cooperat Studies Program, Boston, MA 02130 USA

[21] VA Palo Alto Healthcare Syst, Med Cardiol, Palo Alto, CA 94304 USA

[22] VA Boston Healthcare Syst, Res Serv, Boston, MA 02130 USA

[23] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN 37211 USA

[24] VA San Diego Healthcare Syst, Res Dept, San Diego, CA 92161 USA

[25] UCSD San Diego, Dept Otolaryngol, La Jolla, CA 92093 USA

[26] VA Salt Lake City Hlth Care Syst, VA Informat & Comp Infrastruct, Salt Lake City, UT 84148 USA

[27] Univ Utah, Sch Med, Internal Med Epidemiol, Salt Lake City, UT 84132 USA

[28] Yale Univ, Psychiat Human Genet, New Haven, CT 06520 USA

[29] VA Connecticut Healthcare Syst West Haven, West Haven, CT 06516 USA

[30] VA Tennessee Valley Healthcare Syst, Med Nephrol & Hypertens, Nashville, TN 37232 USA

[31] Vanderbilt Univ, Nashville, TN 37232 USA

[32] Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Cleveland, OH 44106 USA

[33] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA

[34] Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA

[35] Case Western Reserve Univ, Cleveland Inst Computat Biol, Cleveland, OH 44106 USA

[36] VA Providence Healthcare Syst, Med Cardiol Sect, Providence, RI 02908 USA

[37] Brown Univ, Dept Med, Providence, RI 02908 USA

[38] Corporal Michael Crescenz VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA 19104 USA

[39] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA

[40] VA Connecticut Healthcare Syst West Haven, Med, West Haven, CT 06516 USA

[41] VA Portland Hlth Care Syst, Portland, OR 97239 USA

[42] Oregon Hlth & Sci Univ, Knight Canc Inst, Div Hematol & Med Oncol, Portland, OR 97239 USA

[43] Yale Univ, Psychiat, New Haven, CT 06520 USA

[44] VA Connecticut Healthcare Syst West Haven, Psychiat, West Haven, CT 06516 USA

[45] Childrens Hosp Philadelphia, Ctr Spatial & Funct Genom, Philadelphia, PA 19104 USA

[46] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA

[47] Childrens Hosp Philadelphia, Div Human Genet & Endocrinol & Diabet, Philadelphia, PA 19104 USA

[48] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[49] James J Peters VA Med Ctr, Psychiat Mental Illness Res Educ & Clin Ctr, Bronx, NY 10468 USA

[50] Icahn Sch Med Mt Sinai, Bronx, NY 10468 USA

来源：

SCIENCE | 2024年 / 385卷 / 6706期

关键词：

POSITIVE SELECTION; PROSTATE-CANCER; QUALITY-CONTROL; BIOBANK; DISEASE; HEALTH; RISK; PIGMENTATION; EXPRESSION; DESIGN;

D O I：

10.1126/science.adj1182

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

引用

页数：12

共 80 条

[1] The "All of Us" Research Program [J].

Denny J.C. ;

Rutter J.L. ;

Goldstein D.B. ;

Philippakis A. ;

Smoller J.W. ;

Jenkins G. ;

Dishman E. .

NEW ENGLAND JOURNAL OF MEDICINE, 2019, 381 (07) :668-676

[2] A global reference for human genetic variation [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Wang, Jun ;

Wilson, Richard K. ;

Boerwinkle, Eric ;

Doddapaneni, Harsha ;

Han, Yi ;

Korchina, Viktoriya ;

Kovar, Christie ;

Lee, Sandra ;

Muzny, Donna ;

Reid, Jeffrey G. ;

Zhu, Yiming ;

Chang, Yuqi ;

Feng, Qiang ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Lan, Tianming ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Liu, Shengmao ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Tang, Meifang ;

Wang, Bo .

NATURE, 2015, 526 (7571) :68-+

[3] Using Phecodes for Research with the Electronic Health Record: From PheWAS to PheRS [J].

Bastarache, Lisa .

ANNUAL REVIEW OF BIOMEDICAL DATA SCIENCE, VOL 4, 2021, 4 :1-19

[4] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[5] APOL1 G1 genotype modifies the association between HDLC and kidney function in African Americans [J].

Bentley, Amy R. ;

Divers, Jasmin ;

Shriner, Daniel ;

Doumatey, Ayo P. ;

Gutierrez, Orlando M. ;

Adeyemo, Adebowale A. ;

Freedman, Barry I. ;

Rotimi, Charles N. .

BMC GENOMICS, 2015, 16

[6] SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms [J].

Bhutia, Yangzom D. ;

Babu, Ellappan ;

Ramachandran, Sabarish ;

Yang, Shengping ;

Thangaraju, Muthusamy ;

Ganapathy, Vadivel .

BIOCHEMICAL JOURNAL, 2016, 473 :1113-1124

[7] Transethnic Genetic-Correlation Estimates from Summary Statistics [J].

Brown, Brielin C. ;

Ye, Chun Jimmie ;

Price, Alkes L. ;

Zaitlen, Noah .

AMERICAN JOURNAL OF HUMAN GENETICS, 2016, 99 (01) :76-88

[8] An atlas of genetic correlations across human diseases and traits [J].

Bulik-Sullivan, Brendan ;

Finucane, Hilary K. ;

Anttila, Verneri ;

Gusev, Alexander ;

Day, Felix R. ;

Loh, Po-Ru ;

Duncan, Laramie ;

Perry, John R. B. ;

Patterson, Nick ;

Robinson, Elise B. ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (11) :1236-+

[9] LD Score regression distinguishes confounding from polygenicity in genome-wide association studies [J].

Bulik-Sullivan, Brendan K. ;

Loh, Po-Ru ;

Finucane, Hilary K. ;

Ripke, Stephan ;

Yang, Jian ;

Patterson, Nick ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (03) :291-+

[10] Second-generation PLINK: rising to the challenge of larger and richer datasets [J].

Chang, Christopher C. ;

Chow, Carson C. ;

Tellier, Laurent C. A. M. ;

Vattikuti, Shashaank ;

Purcell, Shaun M. ;

Lee, James J. .

GIGASCIENCE, 2015, 4

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