Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility
Open accessAbstract
To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
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LD differences drive differences in effect size estimates from GWAS across populations in proportion to LD between tagging and causal SNP pairs, even when causal effects are the same.
“These LD differences in turn drive differences in effect size estimates (i.e. predictors) from GWAS across populations in proportion to LD between tagging and causal SNP pairs, even when causal effects are the same35,37–40 (Supplementary Note).”
From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [38]
The Results section ('Improved fine-mapping resolution at T2D susceptibility loci'; page unavailable) says that differences in LD with a shared causal variant can produce differences in allelic odds ratios across ancestry groups. The Online Methods ('Fine-mapping analyses'; page unavailable) makes the same point, but neither passage states that the effect-size differences are proportional to LD between tagging and causal SNPs. (LLM, conf=0.84)
Experimental — accuracy not yet measuredLinkage disequilibrium differentiates marginal effect size estimates for polygenic traits across populations, even when causal variants are the same.
“2) linkage disequilibrium (LD) differentiates marginal effect size estimates for polygenic traits across populations, even when causal variants are the same;”
From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [38]
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Self-citation
- Authors
- DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Mahajan, A., Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, South Asian Type 2 Diabetes (SAT2D) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) Consortium, Go, M. J., Zhang, W., Below, J. E., Gaulton, K. J., Ferreira, T., Horikoshi, M., Johnson, A. D., Ng, M. C. Y., Prokopenko, I., Saleheen, D., Wang, X., Zeggini, E., Abecasis, G. R., Adair, L. S., Almgren, P., Atalay, M., Aung, T., Baldassarre, D., Balkau, B., Bao, Y., Barnett, A. H., Barroso, I., Basit, A., Been, L. F., Beilby, J., Bell, G. I., Benediktsson, R., Bergman, R. N., Boehm, B. O., Boerwinkle, E., Bonnycastle, L. L., Burtt, N., Cai, Q., Campbell, H., Carey, J., Cauchi, S., Caulfield, M., Chan, J. C. N., Chang, L.-C., Chang, T.-J., Chang, Y.-C., Charpentier, G., Chen, C.-H., Chen, H., Chen, Y.-T., Chia, K.-S., Chidambaram, M., Chines, P. S., Cho, N. H., Cho, Y. M., Chuang, L.-M., Collins, F. S., Cornelis, M. C., Couper, D. J., Crenshaw, A. T., van Dam, R. M., Danesh, J., Das, D., de Faire, U., Dedoussis, G., Deloukas, P., Dimas, A. S., Dina, C., Doney, A. S. F., Donnelly, P. J., Dorkhan, M., van Duijn, C., Dupuis, J., Edkins, S., Elliott, P., Emilsson, V., Erbel, R., Eriksson, J. G., Escobedo, J., Esko, T., Eury, E., Florez, J. C., Fontanillas, P., Forouhi, N. G., Forsen, T., Fox, C., Fraser, R. M., Frayling, T. M., Froguel, P., Frossard, P., Gao, Y., Gertow, K., Gieger, C., Gigante, B., Grallert, H., Grant, G. B., Groop, L. C., Groves, C. J., Grundberg, E., Guiducci, C., Hamsten, A., Han, B.-G., Hara, K., Hassanali, N., Hattersley, A. T., Hayward, C., Hedman, A. K., Herder, C., Hofman, A., Holmen, O. L., Hovingh, K., Hreidarsson, A. B., Hu, C., Hu, F. B., Hui, J., Humphries, S. E., Hunt, S. E., Hunter, D. J., Hveem, K., Hydrie, Z. I., Ikegami, H., Illig, T., Ingelsson, E., Islam, M., Isomaa, B., Jackson, A. U., Jafar, T., James, A., Jia, W., Jöckel, K.-H., Jonsson, A., Jowett, J. B. M., Kadowaki, T., Kang, H. M., Kanoni, S., Kao, W. H. L., Kathiresan, S., Kato, N., Katulanda, P., Keinanen-Kiukaanniemi, S. M., Kelly, A. M., Khan, H., Khaw, K.-T., Khor, C.-C., Kim, H.-L., Kim, S., Kim, Y. J., Kinnunen, L., Klopp, N., Kong, A., Korpi-Hyövälti, E., Kowlessur, S., Kraft, P., Kravic, J., Kristensen, M. M., Krithika, S., Kumar, A., Kumate, J., Kuusisto, J., Kwak, S. H., Laakso, M., Lagou, V., Lakka, T. A., Langenberg, C., Langford, C., Lawrence, R., Leander, K., Lee, J.-M., Lee, N. R., Li, M., Li, X., Li, Y., Liang, J., Liju, S., Lim, W.-Y., Lind, L., Lindgren, C. M., Lindholm, E., Liu, C.-T., Liu, J. J., Lobbens, S., Long, J., Loos, R. J. F., Lu, W., Luan, J., Lyssenko, V., Ma, R. C. W., Maeda, S., Mägi, R., Männistö, S., Matthews, D. R., Meigs, J. B., Melander, O., Metspalu, A., Meyer, J., Mirza, G., Mihailov, E., Moebus, S., Mohan, V., Mohlke, K. L., Morris, A. D., Mühleisen, T. W., Müller-Nurasyid, M., Musk, B., Nakamura, J., Nakashima, E., Navarro, P., Ng, P.-K., Nica, A. C., Nilsson, P. M., Njølstad, I., Nöthen, M. M., Ohnaka, K., Ong, T. H., Owen, K. R., Palmer, C. N. A., Pankow, J. S., Park, K. S., Parkin, M., Pechlivanis, S., Pedersen, N. L., Peltonen, L., Perry, J. R. B., Peters, A., Pinidiyapathirage, J. M., Platou, C. G. P., Potter, S., Price, J. F., Qi, L., Radha, V., Rallidis, L., Rasheed, A., Rathmann, W., Rauramaa, R., Raychaudhuri, S., Rayner, N. W., Rees, S. D., Rehnberg, E., Ripatti, S., Robertson, N., Roden, M., Rossin, E. J., Rudan, I., Rybin, D., Saaristo, T. E., Salomaa, V., Saltevo, J., Samuel, M., Sanghera, D. K., Saramies, J., Scott, J., Scott, L. J., Scott, R. A., Segrè, A. V., Sehmi, J., Sennblad, B., Shah, N., Shah, S., Shera, A. S., Shu, X. O., Shuldiner, A. R., Sigurðsson, G., Sijbrands, E., Silveira, A., Sim, X., Sivapalaratnam, S., Small, K. S., So, W. Y., Stančáková, A., Stefansson, K., Steinbach, G., Steinthorsdottir, V., Stirrups, K., Strawbridge, R. J., Stringham, H. M., Sun, Q., Suo, C., Syvänen, A.-C., Takayanagi, R., Takeuchi, F., Tay, W. T., Teslovich, T. M., Thorand, B., Thorleifsson, G., Thorsteinsdottir, U., Tikkanen, E., Trakalo, J., Tremoli, E., Trip, M. D., Tsai, F. J., Tuomi, T., Tuomilehto, J., Uitterlinden, A. G., Valladares-Salgado, A., Vedantam, S., Veglia, F., Voight, B. F., Wang, C., Wareham, N. J., Wennauer, R., Wickremasinghe, A. R., Wilsgaard, T., Wilson, J. F., Wiltshire, S., Winckler, W., Wong, T. Y., Wood, A. R., Wu, J.-Y., Wu, Y., Yamamoto, K., Yamauchi, T., Yang, M., Yengo, L., Yokota, M., Young, R., Zabaneh, D., Zhang, F., Zhang, R., Zheng, W., Zimmet, P. Z., Altshuler, D., Bowden, D. W., Cho, Y. S., Cox, N. J., Cruz, M., Hanis, C. L., Kooner, J., Lee, J.-Y., Seielstad, M., Teo, Y. Y., Boehnke, M., Parra, E. J., Chambers, J. C., Tai, E. S., McCarthy, M. I., & Morris, A. P.
- Affiliations
- Centre for Human Genetics (GB)
- Korea National Institute of Health (KR)
- Imperial College London (GB)
- University of Washington (US)
- Framingham Heart Study (US)
- Wake Forest University Health Sciences (US)
- University of Cambridge (GB)
- National University of Singapore (SG)
- Wellcome Sanger Institute (GB)
- University of North Carolina at Chapel Hill (US)
- Lund University (SE)
- University of Eastern Finland (FI)
- University of Milan (IT)
- Université Paris-Sud (FR)
- Shanghai Jiao Tong University (CN)
- National Health Service (GB)
- Baqai Institute of Diabetology and Endocrinology (PK)
- University of Oklahoma Health Sciences Center (US)
- The University of Western Australia (AU)
- University of Chicago (US)
- University of Iceland (IS)
- Cedars-Sinai Medical Center (US)
- Nanyang Technological University (SG)
- Baylor College of Medicine (US)
- National Institutes of Health (US)
- Broad Institute (US)
- Vanderbilt University (US)
- Western General Hospital (GB)
- Queen Mary University of London (GB)
- Chinese University of Hong Kong (HK)
- Institute of Biomedical Sciences, Academia Sinica (TW)
- National Taiwan University Hospital (TW)
- Centre Hospitalier Sud Francilien (FR)
- China Medical University (TW)
- Boston University (US)
- Indian Council of Medical Research (IN)
- Ajou University (KR)
- Seoul National University (KR)
- National Taiwan University (TW)
- Harvard University (US)
- Ealing Hospital NHS Trust (GB)
- Harokopio University of Athens (GR)
- University of Geneva (CH)
- University of Dundee (GB)
- Icelandic Heart Association (IS)
- Essen University Hospital (DE)
- University of Helsinki (FI)
- Mexican Social Security Institute (MX)
- Centre National de la Recherche Scientifique (FR)
- Addenbrooke's Hospital (GB)
- Brigham and Women's Hospital (US)
- University of Edinburgh (GB)
- University of Exeter (GB)
- Center for Non-Communicable Diseases (PK)
- Karolinska University Hospital (SE)
- Helmholtz Munich (DE)
- Karolinska Institutet (SE)
- University of Oxford (GB)
- King's College London (GB)
- The University of Tokyo (JP)
- Deutsches Diabetes-Zentrum e.V. (DE)
- Norwegian University of Science and Technology (NO)
- Amsterdam UMC Location University of Amsterdam (NL)
- University College London (GB)
- Kindai University (JP)
- Aga Khan University (PK)
- Folkhälsans Forskningscentrum (FI)
- University of Michigan (US)
- Baker Heart and Diabetes Institute (AU)
- Johns Hopkins University (US)
- National Center for Global Health and Medicine (JP)
- Oulu University Hospital (FI)
- Agency for Science, Technology and Research (SG)
- Ewha Womans University (KR)
- Finnish Institute for Health and Welfare (FI)
- deCODE Genetics (Iceland) (IS)
- Seinäjoen Keskussairaala (FI)
- Ministry of Health and Quality of Life (MU)
- University of Toronto (CA)
- University of San Carlos (PH)
- Hammersmith Hospital (GB)
- BGI Group (China) (CN)
- Uppsala University (SE)
- University of Tartu (EE)
- University of Bonn (DE)
- Nagoya University (JP)
- Chubu Rosai Hospital (JP)
- UiT The Arctic University of Norway (NO)
- Kyushu University (JP)
- Churchill Hospital (GB)
- University of Minnesota (US)
- University of Kelaniya (LK)
- Kuopio University Hospital (FI)
- Finnish Diabetes Association (FI)
- Central Finland Health Care District (FI)
- South Karelia Central Hospital (FI)
- University of Maryland, Baltimore (US)
- Erasmus MC (NL)
- Universität Ulm (DE)
- Singapore National Eye Center (SG)
- Universität für Weiterbildung Krems (AT)
- Centro Cardiologico Monzino (IT)
- The University of Melbourne (AU)
- Aichi Gakuin University (JP)
- The University of Texas Health Science Center at Houston (US)
- Imperial College Healthcare NHS Trust (GB)
- Corresponding author
- Morris, Andrew D
- Boehnke, Michael
- Parra, Esteban J
- Chambers, John C
- Tai, E Shyong
- McCarthy, Mark I
- Morris, Andrew P
- ORCID
- Mahajan, Anubha
- Zhang, Weihua
- Below, Jennifer E
- Gaulton, Kyle J
- Ferreira, Teresa
- Horikoshi, Momoko
- Johnson, Andrew D
- Ng, Maggie C Y
- Prokopenko, Inga
- Saleheen, Danish
- Wang, Xu
- Zeggini, Eleftheria
- Adair, Linda S
- Almgren, Peter
- Atalay, Mustafa
- Aung, Tin
- Baldassarre, Damiano
- Balkau, Beverley
- Bao, Yuqian
- Barnett, Anthony H
- Basit, Abdul
- Been, Latonya F
- Beilby, John
- Benediktsson, Rafn
- Bergman, Richard N
- Boehm, Bernhard O
- Boerwinkle, Eric
- Bonnycastle, Lori L
- Burtt, Noël
- Cai, Qiuyin
- Caulfield, Mark
- Chan, Juliana C N
- Chang, Li-Ching
- Chang, Tien-Jyun
- Chang, Yi-Cheng
- Charpentier, Guillaume
- Chen, Chien-Hsiun
- Chen, Han
- Chen, Yuan-Tsong
- Chia, Kee-Seng
- Chidambaram, Manickam
- Cho, Nam H
- Cho, Young Min
- Chuang, Lee-Ming
- Collins, Francis S
- Cornelis, Marilyn C
- Couper, David J
- Danesh, John
- Das, Debashish
- Dedoussis, George
- Deloukas, Panos
- Dimas, Antigone S
- Doney, Alex S F
- Donnelly, Peter J
- Dorkhan, Mozhgan
- Dupuis, Josée
- Edkins, Sarah
- Elliott, Paul
- Emilsson, Valur
- Eriksson, Johan G
- Escobedo, Jorge
- Fontanillas, Pierre
- Forouhi, Nita G
- Fox, Caroline
- Fraser, Ross M
- Frayling, Timothy M
- Froguel, Philippe
- Gieger, Christian
- Gigante, Bruna
- Grallert, Harald
- Groop, Leif C
- Grundberg, Elin
- Hamsten, Anders
- Hara, Kazuo
- Hattersley, Andrew T
- Hayward, Caroline
- Herder, Christian
- Hu, Cheng
- Hu, Frank B
- Hui, Jennie
- Humphries, Steve E
- Hunt, Sarah E
- Hveem, Kristian
- Ikegami, Hiroshi
- Ingelsson, Erik
- Jafar, Tazeen
- Jia, Weiping
- Jöckel, Karl-Heinz
- Jonsson, Anna
- Kadowaki, Takashi
- Kang, Hyun Min
- Kanoni, Stavroula
- Kathiresan, Sekar
- Katulanda, Prasad
- Keinanen-Kiukaanniemi, Sirkka M
- Khan, Hassan
- Khaw, Kay-Tee
- Khor, Chiea-Chuen
- Kim, Young Jin
- Kinnunen, Leena
- Kong, Augustine
- Kraft, Peter
- Kristensen, Malene M
- Kumar, Ashish
- Kwak, Soo Heon
- Laakso, Markku
- Lagou, Vasiliki
- Lakka, Timo A
- Langenberg, Claudia
- Langford, Cordelia
- Leander, Karin
- Li, Yun
- Liang, Junbin
- Liju, Samuel
- Lim, Wei-Yen
- Lind, Lars
- Lindgren, Cecilia M
- Lindholm, Eero
- Liu, Ching-Ti
- Long, Jirong
- Loos, Ruth J F
- Lu, Wei
- Luan, Jian'an
- Lyssenko, Valeriya
- Maeda, Shiro
- Mägi, Reedik
- Männistö, Satu
- Meigs, James B
- Melander, Olle
- Metspalu, Andres
- Meyer, Julia
- Moebus, Susanne
- Mohan, Viswanathan
- Mohlke, Karen L
- Morris, Andrew D
- Nakamura, Jiro
- Navarro, Pau
- Nilsson, Peter M
- Njølstad, Inger
- Nöthen, Markus M
- Ohnaka, Keizo
- Owen, Katharine R
- Pankow, James S
- Park, Kyong Soo
- Pechlivanis, Sonali
- Pedersen, Nancy L
- Peltonen, Leena
- Perry, John R B
- Peters, Annette
- Pinidiyapathirage, Janani M
- Price, Jackie F
- Qi, Lu
- Radha, Venkatesan
- Rathmann, Wolfgang
- Raychaudhuri, Soumya
- Rayner, N William
- Rehnberg, Emil
- Ripatti, Samuli
- Roden, Michael
- Rossin, Elizabeth J
- Rudan, Igor
- Rybin, Denis
- Salomaa, Veikko
- Sanghera, Dharambir K
- Scott, James
- Scott, Laura J
- Segrè, Ayellet V
- Sennblad, Bengt
- Shah, Nabi
- Shah, Sonia
- Shu, Xiao Ou
- Shuldiner, Alan R
- Sijbrands, Eric
- Silveira, Angela
- Sim, Xueling
- Sivapalaratnam, Suthesh
- Small, Kerrin S
- So, Wing Yee
- Stirrups, Kathleen
- Strawbridge, Rona J
- Stringham, Heather M
- Sun, Qi
- Suo, Chen
- Takeuchi, Fumihiko
- Tay, Wan Ting
- Thorand, Barbara
- Tikkanen, Emmi
- Tremoli, Elena
- Tsai, Fuu Jen
- Tuomilehto, Jaakko
- Vedantam, Sailaja
- Veglia, Fabrizio
- Voight, Benjamin F
- Wang, Congrong
- Wareham, Nicholas J
- Wilsgaard, Tom
- Wilson, James F
- Winckler, Wendy
- Wong, Tien Yin
- Wood, Andrew R
- Wu, Ying
- Yamamoto, Ken
- Yamauchi, Toshimasa
- Young, Robin
- Zabaneh, Delilah
- Zhang, Fan
- Zhang, Rong
- Zheng, Wei
- Zimmet, Paul Z
- Altshuler, David
- Bowden, Donald W
- Cho, Yoon Shin
- Cox, Nancy J
- Cruz, Miguel
- Hanis, Craig L
- Kooner, Jaspal
- Lee, Jong-Young
- Seielstad, Mark
- Boehnke, Michael
- Parra, Esteban J
- Chambers, John C
- Tai, E Shyong
- McCarthy, Mark I
- Morris, Andrew P
- Venue
- Nature Genetics
- Published
- 2014-02-09
- Volume
- 46
- Issue
- 3
- Pages
- 234-244
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3969612
- OpenAlex
- W2148749248
- Cited by
- 1,034
- References
- 54
- Citations by year
- 2026: 14 · 2025: 32 · 2024: 47 · 2023: 59 · 2022: 81 · 2021: 80 · 2020: 89 · 2019: 105 · 2018: 114 · 2017: 125 · 2016: 152 · 2015: 106 · 2014: 27 · 2013: 1
- FWCI
- 18.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Teesside University Research Portal (Teesside University) (publishedVersion, other-oa)
- Research Explorer (The University of Manchester) (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- AJOU Open Repository (Ajou University) (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Anglia Ruskin Research Online (Anglia Ruskin University) (submittedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
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- eScholarship (California Digital Library) (submittedVersion)
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- Hirsla (Landspítali University Hospital) (submittedVersion)
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- WOS
- Funders
- Wellcome Trust (095552/Z/11/Z, 098017, 098381, WT098017, 095552, WT090367, WT098381, WT090532, 201413, 090532, WT085475, WT081682)
- National Institute for Health and Care Research (NF-SI-0512-10165, NF-SI-0611-10136, NF-SI-0512-10113, NF-SI-0611-10099, NF-SI-0611-10219)
- British Heart Foundation (RG/08/008/25291, RG/08/014/24067)
- European Commission (201413)
- Consejo Nacional de Ciencia y Tecnología
- Instituto Mexicano del Seguro Social
- Instituto de Seguriidad y Servicios Sociales de los Trabadores del Estado
- Novo Nordisk Fonden (NNF12OC1016467, NNF14OC0009819, NNF13OC0005339)
- National Institutes of Health (2r24hd050924-06, UL1TR001079, HG000376, DK085501, DK085584, DK073541, DK062370)
- Canadian Institutes of Health Research
- Medical Research Council (MR/K006584/1, MC_UU_12015/5, MR/L003120/1, MC_UU_12015/2, G0601261, MC_UU_12015/1)
- Japan Society for the Promotion of Science (24591347, 25221307, 24591346, 23591328, 23591327, 24390169)
- National Human Genome Research Institute (R56HG000376, R01HG000376, HG000376, T32HG000040)
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK085584, U01DK085501, R01DK072193, DK-085501, U01DK062370, DK085545, U01DK085545, R56DK062370, R01DK073541, R01DK078616, K24DK080140, DK-085584, DK-073541, DK-062370, R01DK093757, R01DK062370)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R24 HD-050924)
- FP7 Health (201413, HEALTH-F4-2007-201413)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- type 2 diabetes, genetic susceptibility, genetic architecture, disease susceptibility loci, fine mapping, ethnic ancestry, East Asian ancestry, South Asian ancestry, European ancestry
- MeSH terms
- Alleles, Diabetes Mellitus, Type 2, Hispanic or Latino, Humans, Risk Factors, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, Asian People, Genome-Wide Association Study
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