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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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“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]
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“2) linkage disequilibrium (LD) differentiates marginal effect size estimates for polygenic traits across populations, even when causal variants are the same;”
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Self-citation
Metadata
- 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)
- Erasmus MC (NL)
- 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)
- 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
- van Dam, Rob M
- Danesh, John
- Das, Debashish
- Dedoussis, George
- Deloukas, Panos
- Dimas, Antigone S
- Doney, Alex S F
- Donnelly, Peter J
- Dorkhan, Mozhgan
- van Duijn, Cornelia
- 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
- FWCI
- 18.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
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- Spiral (Imperial College London) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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