dc.contributor.author | Timpson, NJ | en_US |
dc.contributor.author | Lindgren, CM | en_US |
dc.contributor.author | Weedon, MN | en_US |
dc.contributor.author | Randall, J | en_US |
dc.contributor.author | Ouwehand, WH | en_US |
dc.contributor.author | Strachan, DP | en_US |
dc.contributor.author | Rayner, NW | en_US |
dc.contributor.author | Walker, M | en_US |
dc.contributor.author | Hitman, GA | en_US |
dc.contributor.author | Doney, ASF | en_US |
dc.contributor.author | Palmer, CNA | en_US |
dc.contributor.author | Morris, AD | en_US |
dc.contributor.author | Hattersley, AT | en_US |
dc.contributor.author | Zeggini, E | en_US |
dc.contributor.author | Frayling, TM | en_US |
dc.contributor.author | McCarthy, MI | en_US |
dc.date.accessioned | 2016-08-30T11:21:36Z | |
dc.date.issued | 2009-02 | en_US |
dc.date.submitted | 2016-08-03T17:41:51.642Z | |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/14900 | |
dc.description.abstract | OBJECTIVE: 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.sponsorship | Collection 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.extent | 505 - 510 | en_US |
dc.language | eng | en_US |
dc.relation.ispartof | Diabetes | en_US |
dc.rights | Readers 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.subject | Adiposity | en_US |
dc.subject | Body Mass Index | en_US |
dc.subject | Diabetes Mellitus, Type 2 | en_US |
dc.subject | Genetic Heterogeneity | en_US |
dc.subject | Genetic Predisposition to Disease | en_US |
dc.subject | Genome-Wide Association Study | en_US |
dc.subject | Humans | en_US |
dc.subject | Obesity | en_US |
dc.subject | Polymorphism, Single Nucleotide | en_US |
dc.title | Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. | en_US |
dc.type | Article | |
dc.identifier.doi | 10.2337/db08-0906 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/19056611 | en_US |
pubs.issue | 2 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 58 | en_US |