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University of Groningen a Variant in CDKAL1 Influences Insulin Response and Risk of Type 2 Diabetes Steinthorsdottir, V.; Thorle

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University of Groningen a Variant in CDKAL1 Influences Insulin Response and Risk of Type 2 Diabetes Steinthorsdottir, V.; Thorle University of Groningen A variant in CDKAL1 influences insulin response and risk of type 2 diabetes Steinthorsdottir, V.; Thorleifsson, G.; Reynisdottir, I.; Benediktsson, R.; Jonsdottir, T.; Walters, G.B.; Styrkarsdottir, U.; Gretarsdottir, S.; Emilsson, V.; Ghosh, S. Published in: Nature Genetics DOI: 10.1038/ng2043 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2007 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Steinthorsdottir, V., Thorleifsson, G., Reynisdottir, I., Benediktsson, R., Jonsdottir, T., Walters, G. B., Styrkarsdottir, U., Gretarsdottir, S., Emilsson, V., Ghosh, S., Baker, A., Snorradottir, S., Bjarnason, H., Ng, M. C., Hansen, T., Bagger, Y., Wilensky, R. L., Reilly, M. P., Adeyemo, A., ... Stefansson, K. (2007). A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nature Genetics, 39(6), 770- 775. https://doi.org/10.1038/ng2043 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 01-10-2021 LETTERS A variant in CDKAL1 influences insulin response and risk of type 2 diabetes Valgerdur Steinthorsdottir1,15, Gudmar Thorleifsson1,15, Inga Reynisdottir1, Rafn Benediktsson2,3, Thorbjorg Jonsdottir1, G Bragi Walters1, Unnur Styrkarsdottir1, Solveig Gretarsdottir1, Valur Emilsson1, Shyamali Ghosh1, Adam Baker1, Steinunn Snorradottir1, Hjordis Bjarnason1, Maggie C Y Ng4, Torben Hansen5, Yu Bagger6, Robert L Wilensky7, Muredach P Reilly7, Adebowale Adeyemo8, Yuanxiu Chen8, Jie Zhou8, Vilmundur Gudnason3, Guanjie Chen8, Hanxia Huang8, Kerrie Lashley8, Ayo Doumatey8, Wing-Yee So4, Ronald C Y Ma4, Gitte Andersen5, Knut Borch-Johnsen5,9,10, Torben Jorgensen10, Jana V van Vliet-Ostaptchouk11, Marten H Hofker11,12, Cisca Wijmenga13,14, Claus Christiansen6, Daniel J Rader7, Charles Rotimi8, Mark Gurney1, http://www.nature.com/naturegenetics Juliana C N Chan4, Oluf Pedersen5,9,Gunnar Sigurdsson2,3, Jeffrey R Gulcher1, Unnur Thorsteinsdottir1, Augustine Kong1 & Kari Stefansson1 We conducted a genome-wide association study for type 2 two-marker haplotypes identified as efficient surrogates (r2 > 0.8) for diabetes (T2D) in Icelandic cases and controls, and we found a set of SNPs that were not included on the Hap300 chip but that were that a previously described variant in the transcription factor typed in the HapMap project4. In addition to analyzing the entire group 7-like 2 gene (TCF7L2) gene conferred the most significant risk. of individuals with T2D, separately we tested 700 non-obese individuals In addition to confirming two recently identified risk variants1, with T2D and 531 obese individuals with T2D for association. Overall, we identified a variant in the CDKAL1 gene that was associated we performed a total of 1,959,075 (653,025 variants × 3 phenotypes) Nature Publishing Group Group Nature Publishing 7 with T2D in individuals of European ancestry (allele-specific tests. The results were adjusted for relatedness between individuals and odds ratio (OR) = 1.20 (95% confidence interval, 1.13–1.27), potential population stratification by genomic control5 (see Methods). 200 −9 © P = 7.7 × 10 ) and individuals from Hong Kong of Han A previously identified SNP, rs7903146, in TCF7L2 gave the most signifi- Chinese ancestry (OR = 1.25 (1.11–1.40), P = 0.00018). cant results, with OR = 1.38 and P = 1.82 × 10−10 in all individuals with The genotype OR of this variant suggested that the effect T2D. Although no other SNP or haplotype was significant after adjust- was substantially stronger in homozygous carriers than ment for the number of tests performed, we observed more borderline- in heterozygous carriers. The ORs for homozygotes were significant signals than expected by chance alone (Supplementary Fig. 1 1.50 (1.31–1.72) and 1.55 (1.23–1.95) in the European online). A comprehensive follow-up strategy would require genotyping and Hong Kong groups, respectively. The insulin response a large number of SNPs6, so we decided to pursue the top signals quickly for homozygotes was approximately 20% lower than for in a fast-tracking effort. heterozygotes or noncarriers, suggesting that this variant For each phenotype tested, we selected all single SNPs and two-marker confers risk of T2D through reduced insulin secretion. haplotypes with P < 0.00005 for replication in a case-control sample from Denmark (Denmark B). After eliminating redundant markers, We recently described a variant in TCF7L2 associated with T2D2,3. To we selected a total of 46 SNPs for replication (Supplementary Table 1 look for additional genetic variants that increase the risk of develop- online). In addition, we included the five most significant nonsynony- ing T2D, we performed a genome-wide association study on Icelandic mous SNPs present on the Illumina Hap300 chip. Of these 51 SNPs, we individuals with T2D using the Illumina HumanHap300 chip. We tested successfully genotyped 47 in 1,110 Danish T2D cases and 2,272 controls. 313,179 SNPs individually for association with T2D in a sample of 1,399 In the Danish group of all individuals with T2D, SNPs rs7756992 and individuals with T2D and 5,275 controls. We tested an additional 339,846 rs13266634 stood out and were significantly replicated (P = 0.00013 and 1deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland. 2Landspitali-University Hospital, 101 Reykjavik, Iceland. 3Icelandic Heart Association, 201 Kopavogur, Iceland. 4Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. 5Steno Diabetes Center, DK-2820 Copenhagen, Denmark. 6Center for Clinical and Basic Research A/S, DK-2750 Ballerup, Denmark. 7University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. 8National Human Genome Center, Howard University, Department of Community and Family Medicine, Washington, DC 20060, USA. 9Faculty of Health Science, University of Aarhus, DK-8000 Aarhus, Denmark. 10Research Centre for Prevention and Health, Glostrup University Hospital, DK-2600 Glostrup, Denmark. 11Department of Molecular Genetics, Maastricht University, 6200 MD Maastricht, The Netherlands. 12Department of Pathology and Laboratory Medicine and 13Department of Genetics, University Medical Center Groningen (UMCG), 9700 RB Groningen, The Netherlands. 14Complex Genetics Section, Department of Biomedical Genetics, University Medical Centre Utrecht, 3508 AB Utrecht, The Netherlands. 15These authors contributed equally to this work. Correspondence should be addressed to K.S. ([email protected]) or V.S. ([email protected]). Received 14 March; accepted 17 April; published online 26 April 2007; doi:10.1038/ng2043 770 VOLUME 39 | NUMBER 6 | JUNE 2007 | NATURE GENETICS LETTERS Table 1 Association results for rs7756992 and rs13266634 in five T2D case-control groups of European ancestry and in case-control groups from Hong Kong and West Africa Controls Affected individuals Frq AA/Aa/aab Frq AA/Aa/aab OR (95% c.i.) P valuevalue Iceland (1,399/ 5,275) rs7756992 (G) 0.232 3,107/1,887/277 0.270 751/539/108 1.23 (1.10–1.37) 0.00021 rs13266634 (C) 0.646 700/2,339/2,236 0.685 143/596/660 1.19 (1.08–1.31) 0.0006 Denmark A (263/597) rs7756992 (G) 0.297 292/255/50 0.331 111/99/30 1.17 (0.93–1.47) 0.18 rs13266634 (C) 0.686 62/242/279 0.672 35/99/124 0.94 (0.75–1.17) 0.58 Denmark B (1,359/4,825) rs7756992 (G) 0.279 2,503/1,884/394 0.320 624/564/144 1.21 (1.10–1.33) 0.000054 rs13266634 (C) 0.673 555/1,997/2,204 0.692 128/566/639 1.09 (0.99–1.19) 0.073 Philadelphia (447/950) rs7756992 (G) 0.262 492/331/68 0.295 216/174/40 1.18 (0.98–1.42) 0.073 rs13266634 (C) 0.678 85/377/387 0.760 29/145/249 1.51 (1.25–1.81) 1.5 × 10−5 The Netherlands (368/915) rs7756992 (G) 0.270 475/359/63 0.280 186/138/30 1.05 (0.86–1.29) 0.64 rs13266634 (C) 0.717 80/349/469 0.736 28/136/199 1.10 (0.91–1.33) 0.33 European ancestry combineda (3,836/12,562) −9 http://www.nature.com/naturegenetics rs7756992 (G) 0.258 0.295 1.20 (1.13–1.27) 7.7 × 10 rs13266634 (C) 0.666 0.700 1.15 (1.08–1.22) 3.3 × 10−6 Hong Kong (1,457/986) rs7756992 (G) 0.462 293/446/220 0.517 351/681/400 1.25 (1.11–1.40) 0.00018 rs13266634 (C) 0.523 214/497/259 0.566 276/686/464 1.19 (1.06–1.33) 0.0035 West Africaa (865/1,106) rs7756992 (G) 0.612 160/499/397 0.625 137/349/344 1.02 (0.92–1.14) 0.72 rs13266634 (C) 0.962 4/74/1004 0.971 2/45/804 1.26 (0.88–1.81) 0.21 Numbers in parentheses next to population names represent the number of individuals with T2D and controls, respectively.
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