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Adiposity-Related Heterogeneity in Patterns of Type 2 Diabetes Susceptibility Observed in Genome-Wide Association Data.
- Source :
- Diabetes; Feb2009, Vol. 58 Issue 2, p505-510, 6p, 3 Charts, 1 Graph
- Publication Year :
- 2009
-
Abstract
- OBJECTIVE--This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genomewide 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/m²). 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-<superscript>-13</superscript>), 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<superscript>-14</superscript>). These patterns, continued by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: P<subscript>DIFF</subscript> = 1.4 x 10<superscript>-7</superscript>; TCFTL2: P<subscript>DIFF</subscript> = 4.0 x 10<superscript>-6</superscript>). 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 SLC3OA8 locus alone (RR[sub obese] 1.08 [1.011.15]; RR[sub nonobese] 1.18 [1.10-1.27]: P<subscript>DIFF</subscript> = 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. Diabetes 58:505-510, 2009 [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 58
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 36865276
- Full Text :
- https://doi.org/10.2337/db08-0906