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. 2010 Mar;59(3):741-6.
doi: 10.2337/db09-0920. Epub 2009 Dec 22.

Detailed investigation of the role of common and low-frequency WFS1 variants in type 2 diabetes risk

Katherine A Fawcett  1 , Eleanor Wheeler, Andrew P Morris, Sally L Ricketts, Göran Hallmans, Olov Rolandsson, Allan Daly, Jon Wasson, Alan Permutt, Andrew T Hattersley, Benjamin Glaser, Paul W Franks, Mark I McCarthy, Nicholas J Wareham, Manjinder S Sandhu, Inês Barroso
Affiliations

Detailed investigation of the role of common and low-frequency WFS1 variants in type 2 diabetes risk

Katherine A Fawcett et al. Diabetes. 2010 Mar.

Abstract

Objective: Wolfram syndrome 1 (WFS1) single nucleotide polymorphisms (SNPs) are associated with risk of type 2 diabetes. In this study we aimed to refine this association and investigate the role of low-frequency WFS1 variants in type 2 diabetes risk.

Research design and methods: For fine-mapping, we sequenced WFS1 exons, splice junctions, and conserved noncoding sequences in samples from 24 type 2 diabetic case and 68 control subjects, selected tagging SNPs, and genotyped these in 959 U.K. type 2 diabetic case and 1,386 control subjects. The same genomic regions were sequenced in samples from 1,235 type 2 diabetic case and 1,668 control subjects to compare the frequency of rarer variants between case and control subjects.

Results: Of 31 tagging SNPs, the strongest associated was the previously untested 3' untranslated region rs1046320 (P = 0.008); odds ratio 0.84 and P = 6.59 x 10(-7) on further replication in 3,753 case and 4,198 control subjects. High correlation between rs1046320 and the original strongest SNP (rs10010131) (r2 = 0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (minor allele frequency [MAF] <0.01) nonsynonymous variants between type 2 diabetic case and control subjects (P = 0.79). Two intermediate frequency (MAF 0.01-0.05) nonsynonymous changes also showed no statistical association with type 2 diabetes.

Conclusions: We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing.

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Figures

FIG. 1.
FIG. 1.
Meta-analysis of rs1046320 in U.K., Ashkenazi, ADDITION/Ely, and Västerbotten case-control studies. The overall OR is 0.856 (95% CI 0.804–0.912), P = 1.25 × 10−6. Summary statistics from previously published work (11) show that rs10010131 has a comparable overall OR of 0.854 (0.800–0.912), P = 2.58 ×10−6, in the same populations. ES, effect size.
FIG. 2.
FIG. 2.
The statistical strength of the association of WFS1 tagging (◇) and imputed (○) SNPs in the context of estimated recombination rates (blue line) and pairwise correlation between rs10010131 and surrounding markers. Red represents r2 > 0.85, orange represents 0.5 < r2 < 0.85, yellow represents 0.2 < r2 < 0.5, and white represents r2 < 0.2.
See this image and copyright information in PMC

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