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dc.contributor.authorTimpson, NJen_US
dc.contributor.authorLindgren, CMen_US
dc.contributor.authorWeedon, MNen_US
dc.contributor.authorRandall, Jen_US
dc.contributor.authorOuwehand, WHen_US
dc.contributor.authorStrachan, DPen_US
dc.contributor.authorRayner, NWen_US
dc.contributor.authorWalker, Men_US
dc.contributor.authorHitman, GAen_US
dc.contributor.authorDoney, ASFen_US
dc.contributor.authorPalmer, CNAen_US
dc.contributor.authorMorris, ADen_US
dc.contributor.authorHattersley, ATen_US
dc.contributor.authorZeggini, Een_US
dc.contributor.authorFrayling, TMen_US
dc.contributor.authorMcCarthy, MIen_US
dc.date.accessioned2016-08-30T11:21:36Z
dc.date.issued2009-02en_US
dc.date.submitted2016-08-03T17:41:51.642Z
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/14900
dc.description.abstractOBJECTIVE: This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genome-wide patterns of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes. RESEARCH DESIGN AND METHODS: We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938 control subjects: 393,453 single-nucleotide polymorphisms [SNPs]) after stratifying case subjects (into "obese" and "nonobese") according to median BMI (30.2 kg/m(2)). Replication of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in type 2 diabetes association signal was sought in additional samples. RESULTS: In the "obese-type 2 diabetes" scan, FTO variants had the strongest type 2 diabetes effect (rs8050136: relative risk [RR] 1.49 [95% CI 1.34-1.66], P = 1.3 x 10(-13)), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 [1.09-1.35], P = 0.001). This situation was reversed in the "nonobese" scan, with FTO association undetectable (RR 1.07 [0.97-1.19], P = 0.19) and TCF7L2 predominant (RR 1.53 [1.37-1.71], P = 1.3 x 10(-14)). These patterns, confirmed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: P(DIFF) = 1.4 x 10(-7); TCF7L2: P(DIFF) = 4.0 x 10(-6)). Other signals displaying evidence of effect size heterogeneity in the genome-wide analyses (on chromosomes 3, 12, 15, and 18) did not replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for effect size heterogeneity for the SLC30A8 locus alone (RR(obese) 1.08 [1.01-1.15]; RR(nonobese) 1.18 [1.10-1.27]: P(DIFF) = 0.04). CONCLUSIONS: This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within type 2 diabetes.en_US
dc.description.sponsorshipCollection of the U.K. type 2 diabetes case subjects was supported by Diabetes UK, British Diabetic Association Research, and the U.K. Medical Research Council (Biomedical Collections Strategic Grant G0000649). The U.K. Type 2 Diabetes Genetics Consortium collection was supported by the Wellcome Trust (Biomedical Collections Grant GR072960). The GWA genotyping was supported by the Wellcome Trust (076113) and replication genotyping by the European Commission (EURODIA LSHG-CT-2004-518153), MRC (Project Grant G016121), Wellcome Trust, Peninsula Medical School, and Diabetes UK. M.I.M. received support from the Oxford National Institute for Health Research Biomedical Research Centre. E.Z. is a Wellcome Trust Research Career Development Fellow. M.N.W. is a Vandervell Foundation Research Fellow. A.T.H. is a Wellcome Trust Research Leave Fellow. The Wellcome Trust provides core support for the U.K. Type 2 Diabetes Case Control Collection. C.M.L. is a Nuffield Department of Medicine Scientific Leadership Fellow. N.J.T. was funded by the MRC CAiTE (grant 90600705)en_US
dc.format.extent505 - 510en_US
dc.languageengen_US
dc.relation.ispartofDiabetesen_US
dc.rightsReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details.
dc.rights© 2009 by the American Diabetes Association
dc.subjectAdiposityen_US
dc.subjectBody Mass Indexen_US
dc.subjectDiabetes Mellitus, Type 2en_US
dc.subjectGenetic Heterogeneityen_US
dc.subjectGenetic Predisposition to Diseaseen_US
dc.subjectGenome-Wide Association Studyen_US
dc.subjectHumansen_US
dc.subjectObesityen_US
dc.subjectPolymorphism, Single Nucleotideen_US
dc.titleAdiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data.en_US
dc.typeArticle
dc.identifier.doi10.2337/db08-0906en_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/19056611en_US
pubs.issue2en_US
pubs.notesNot knownen_US
pubs.publication-statusPublisheden_US
pubs.volume58en_US


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