Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis
Open accessAbstract
By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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Over 60 genetic loci have been convincingly associated with T2D.
“At the time of writing, over 60 genetic loci have been convincingly associated with T2D”
From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [8]
The Discussion states that the number of confirmed T2D loci stood at 38 when the source paper was written, not over 60. The paper cannot establish a later count at the citing document’s time of writing. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe great majority of T2D-associated genetic loci are involved in β-cell biology.
“the great majority in some way involved in β-cell biology, underscoring the importance of β-cell dysfunction in T2D pathogenesis ( 8 , 9 ).”
From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [8]
In Results, under “Understanding the biology of T2D-susceptibility loci” (page not provided), the paper says common T2D risk alleles more often act through beta-cell dysfunction. That supports the emphasis on beta-cell biology, but not the stronger claim that the great majority of loci are involved: the paper identifies loci primarily affecting insulin action and says the mechanisms at other loci remain unclear. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe large-scale impact of large numbers of common variants may be a general feature of human complex traits.
“Indeed, the large-scale impact of large numbers of common variants may be a general feature of human complex traits 70–77”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [72]
Hypothesized genetic architectures consisting entirely of rare variants are inconsistent with the data for AD, ASD, BIP, and SCZ (as well as for multiple other complex biomedical diseases).
“Hypothesized genetic architectures consisting entirely of rare variants are inconsistent with the data for AD, ASD, BIP, and SCZ (as well as for multiple other complex biomedical diseases). 70–77”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [72]
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“Whenever possible, we used the effect sizes from stage 2 of DIAGRAM+ [11].”
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Self-citationBillings, L. K., Jablonski, K. A., Warner, A. S., Cheng, Y.-C., McAteer, J. B., Tipton, L., Shuldiner, A. R., Ehrmann, D. A., Manning, A. K., Dabelea, D., et al. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-3429 · Cited by 20 · see citing works
Self-citationHNF1A gene p.I27L is associated with co-existing preeclampsia in gestational diabetes mellitus
Beysel, S., Pinarli, F. A., Eyerci, N., Kizilgul, M., Hepsen, S., Alhan, A., Kan, S., Caliskan, M., Bozkurt, E., & Cakal, E. (2020) · Gynecological Endocrinology · doi:10.1080/09513590.2019.1698023 · Cited by 12 · see citing works
Genetic variation within transcriptional regulatory elements and its implications for human disease
Rada-Iglesias, A. (2014) · Biological Chemistry · doi:10.1515/hsz-2014-0109 · Cited by 7 · see citing works
Cheng, C.-Y., Reich, D., Haiman, C. A., Tandon, A., Patterson, N., Elizabeth, S., Akylbekova, E. L., Brancati, F. L., Coresh, J., Boerwinkle, E., et al. (2012) · PLoS ONE · doi:10.1371/annotation/52e53d8e-a4bd-4419-951a-75ddcbaf6c5d · Cited by 2 · see citing works
Self-citationShepherd, A. I., Wilkerson, D. P., Dobson, L., Kelly, J., Winyard, P. G., Jones, A. M., Benjamin, N., Shore, A. C., & Gilchrist, M. (2015) · Nitric Oxide · doi:10.1016/j.niox.2015.01.002 · Cited by 88 · see citing works
- Authors
- The MAGIC investigators, Voight, B. F., The GIANT Consortium, Scott, L. J., Steinthorsdottir, V., Morris, A. P., Dina, C., Welch, R. P., Zeggini, E., Huth, C., Aulchenko, Y. S., Thorleifsson, G., McCulloch, L. J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C. J., Raychaudhuri, S., McCarroll, S. A., Langenberg, C., Hofmann, O. M., Dupuis, J., Qi, L., Segrè, A. V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A. J., Blagieva, R., Boerwinkle, E., Bonnycastle, L. L., Boström, K. B., Bravenboer, B., Bumpstead, S., Burtt, N. P., Charpentier, G., Chines, P. S., Cornelis, M., Couper, D. J., Crawford, G., Doney, A. S. F., Elliott, K. S., Elliott, A. L., Erdos, M. R., Fox, C. S., Franklin, C. S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C. J., Guiducci, C., Hadjadj, S., Hassanali, N., Herder, C., Isomaa, B., Jackson, A. U., Johnson, P. R. V., Jørgensen, T., Kao, W. H. L., Klopp, N., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lindgren, C. M., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M. A., Narisu, N., Nilsson, P., Owen, K. R., Payne, F., Perry, J. R. B., Petersen, A.-K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N. W., Robertson, N. R., Rocheleau, G., Roden, M., Sampson, M. J., Saxena, R., Shields, B. M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H. M., Sun, Q., Swift, A. J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R. M., van Haeften, T. W., van Herpt, T., van Vliet-Ostaptchouk, J. V., Walters, G. B., Weedon, M. N., Wijmenga, C., Witteman, J., Bergman, R. N., Cauchi, S., Collins, F. S., Gloyn, A. L., Gyllensten, U., Hansen, T., Hide, W. A., Hitman, G. A., Hofman, A., Hunter, D. J., Hveem, K., Laakso, M., Mohlke, K. L., Morris, A. D., Palmer, C. N. A., Pramstaller, P. P., Rudan, I., Sijbrands, E., Stein, L. D., Tuomilehto, J., Uitterlinden, A., Walker, M., Wareham, N. J., Watanabe, R. M., Abecasis, G. R., Boehm, B. O., Campbell, H., Daly, M. J., Hattersley, A. T., Hu, F. B., Meigs, J. B., Pankow, J. S., Pedersen, O., Wichmann, H.-E., Barroso, I., Florez, J. C., Frayling, T. M., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J. F., Illig, T., Froguel, P., van Duijn, C. M., Stefansson, K., Altshuler, D., Boehnke, M., & McCarthy, M. I.
- Affiliations
- Broad Institute (US)
- deCODE Genetics (Iceland) (IS)
- Centre National de la Recherche Scientifique (FR)
- Centre for Human Genetics (GB)
- Erasmus MC (NL)
- Ontario Institute for Cancer Research (CA)
- Harvard University (US)
- Boston University (US)
- Inserm (FR)
- University of Oxford (GB)
- Universität Ulm (DE)
- National Institutes of Health (US)
- Catharina Ziekenhuis (NL)
- Brigham and Women's Hospital (US)
- University of North Carolina at Chapel Hill (US)
- University of Michigan (US)
- Helmholtz Munich (DE)
- Deutsches Diabetes-Zentrum e.V. (DE)
- University of Copenhagen (DK)
- Johns Hopkins University (US)
- Aarhus University (DK)
- Norwegian University of Science and Technology (NO)
- Lund University (SE)
- Wellcome Sanger Institute (GB)
- University of Exeter (GB)
- McGill University and Génome Québec Innovation Centre (CA)
- National Health Service (GB)
- National University Hospital of Iceland (IS)
- Folkhälsans Forskningscentrum (FI)
- University Medical Center Groningen (NL)
- University of Southern California (US)
- Uppsala University (SE)
- University of London (GB)
- Eurac Research (IT)
- University of Helsinki (FI)
- Addenbrooke's Hospital (GB)
- University of Minnesota (US)
- Hammersmith Hospital (GB)
- Corresponding author
- Wilson, James F
- Illig, Thomas
- Froguel, Philippe
- Altshuler, David
- Boehnke, Michael
- McCarthy, Mark I
- ORCID
- Voight, Benjamin F
- Scott, Laura J
- Morris, Andrew P
- Welch, Ryan P
- Zeggini, Eleftheria
- Huth, Cornelia
- Aulchenko, Yurii S
- McCulloch, Laura J
- Ferreira, Teresa
- Grallert, Harald
- Amin, Najaf
- Wu, Guanming
- Willer, Cristen J
- Raychaudhuri, Soumya
- Langenberg, Claudia
- Hofmann, Oliver M
- Dupuis, Josée
- Qi, Lu
- Segrè, Ayellet V
- Navarro, Pau
- Ardlie, Kristin
- Balkau, Beverley
- Benediktsson, Rafn
- Bennett, Amanda J
- Boerwinkle, Eric
- Bonnycastle, Lori L
- Boström, Kristina Bengtsson
- Bravenboer, Bert
- Charpentier, Guillaume
- Couper, David J
- Doney, Alex S F
- Elliott, Katherine S
- Erdos, Michael R
- Fox, Caroline S
- Gieger, Christian
- Grarup, Niels
- Griffin, Simon
- Hadjadj, Samy
- Herder, Christian
- Jackson, Anne U
- Jørgensen, Torben
- Kong, Augustine
- Kraft, Peter
- Lauritzen, Torsten
- Li, Man
- Lindgren, Cecilia M
- Lyssenko, Valeriya
- Marre, Michel
- Meitinger, Thomas
- Narisu, Narisu
- Nilsson, Peter
- Owen, Katharine R
- Payne, Felicity
- Perry, John R B
- Prokopenko, Inga
- Rathmann, Wolfgang
- Rayner, N William
- Rocheleau, Ghislain
- Roden, Michael
- Saxena, Richa
- Shields, Beverley M
- Strassburger, Klaus
- Stringham, Heather M
- Sun, Qi
- Thorand, Barbara
- Walters, G Bragi
- Weedon, Michael N
- Wijmenga, Cisca
- Bergman, Richard N
- Collins, Francis S
- Gloyn, Anna L
- Gyllensten, Ulf
- Hansen, Torben
- Hitman, Graham A
- Hveem, Kristian
- Laakso, Markku
- Mohlke, Karen L
- Morris, Andrew D
- Pramstaller, Peter P
- Rudan, Igor
- Sijbrands, Eric
- Stein, Lincoln D
- Tuomilehto, Jaakko
- Walker, Mark
- Wareham, Nicholas J
- Watanabe, Richard M
- Abecasis, Gonçalo R
- Boehm, Bernhard O
- Daly, Mark J
- Hattersley, Andrew T
- Hu, Frank B
- Meigs, James B
- Pankow, James S
- Pedersen, Oluf
- Wichmann, H-Erich
- Barroso, Inês
- Frayling, Timothy M
- Groop, Leif
- Wilson, James F
- Froguel, Philippe
- Altshuler, David
- Boehnke, Michael
- McCarthy, Mark I
- Venue
- Nature Genetics
- Published
- 2010-06-27
- Volume
- 42
- Issue
- 7
- Pages
- 579-589
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3080658
- OpenAlex
- W2141642891
- Cited by
- 1,761
- References
- 71
- Citations by year
- 2026: 18 · 2025: 24 · 2024: 49 · 2023: 43 · 2022: 65 · 2021: 86 · 2020: 54 · 2019: 70 · 2018: 87 · 2017: 124 · 2016: 140 · 2015: 163 · 2014: 166 · 2013: 211 · 2012: 225
- FWCI
- 120.40
- Type
- journal article
- Language
- en
- Update notices
- erratum (2011-03-29)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Open Research (University of Surrey) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Wellcome Trust (072960, 81696, 083270, 081682, 075491, 064890, 088885, 086596, 077016, 079557, 090532, 076113)
- National Institute for Health and Care Research (DHCS/07/07/008)
- National Institutes of Health (n01hc55021-47-0-1, n01hc55020-39-0-0, n01hc55016-37-0-0, n01hc055022-024, n01hc55019-35-0-1, 5k99hl094535-02, n01hc55018-38-0-1, n01hc25195-41-0-1, n01hc55015-48-0-1)
- Medical Research Council (MC_U106179474, G0601261, MRC G0701863)
- National Heart, Lung, and Blood Institute (N01-HC55022, N01 HC055016, N01-HC-55018, N01 HC 55020, N01‐HC25195, N01 HC 55019, R01 HL-59367, N01 HC055020, 1K99HL094535-01A1, N02- HL-64278, N01 HC055018, N01-HC-025195, N01-HC55016, R01HL087641, N01 HC055022, R01HL059367, N01 HC055019, K99-HL094535, N01‐HC‐55015, N01-HC55021, N01 HC055021, N01 HC055015, R01HL086694)
- National Institute on Drug Abuse (U54DA021519)
- National Human Genome Research Institute (Z01HG000024, U01HG004399, U01HG004402, U01HG004171)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK073490, DK-072193, DK078616, R01DK072193, DK073490, U01DK062370, R01DK058845, R01DK069922, K23 DK65978, R56DK062370, DK069922, R01DK078616, K24DK080140, U01DK078616, K23DK065978, R01DK029867, DK-062370, DK58845, UM1DK078616, R01DK062370)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR055688)
- National Center for Research Resources (UL1RR025005)
- 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 loci, beta-cell function, insulin action, cell cycle regulation, KCNQ1, X chromosome, DUSP9, HNF1A, monogenic diabetes, European ancestry, complex traits
- MeSH terms
- Blood Glucose, Diabetes Mellitus, Type 2, Fasting, Humans, Meta-Analysis as Topic, Genome, Human, Gene Dosage, Genetic Heterogeneity, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Gene Expression Profiling, Hepatocyte Nuclear Factor 1-alpha, KCNQ1 Potassium Channel, Dual-Specificity Phosphatases, Mitogen-Activated Protein Kinase Phosphatases, Genome-Wide Association Study
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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.
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