Detailed Investigation of the Role of Common and Low-Frequency WFS1 Variants in Type 2 Diabetes Risk

  1. Inês Barroso1
  1. 1Metabolic Disease Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, U.K.;
  2. 2Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.;
  3. 3Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, U.K.;
  4. 4Section for Nutritional Research, Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden;
  5. 5Section for Family Medicine, Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden;
  6. 6Department of Medicine, Metabolism, Diabetes and Lipid Research Division, Washington University School of Medicine, Saint Louis, Missouri;
  7. 7Department of Internal Medicine, Metabolism, Diabetes and Lipid Research Division, Washington University School of Medicine, Saint Louis, Missouri;
  8. 8Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K.;
  9. 9Endocrine and Metabolism Service, The Hadassah Hebrew University Medical Center, Jerusalem, Israel;
  10. 10Section for Medicine, Department of Public Health & Clinical Medicine, Genetic Epidemiology & Clinical Research Group, Umeå University Hospital, Umeå, Sweden;
  11. 11Section for Nutritional Research, Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden;
  12. 12Oxford Centre for Diabetes Endocrinology & Metabolism, Churchill Hospital, University of Oxford, Oxford, U.K.;
  13. 13Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Headington, Oxford, U.K.;
  14. 14Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford, U.K.;
  15. 15Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge, U.K.
  1. Corresponding author: Inês Barroso, ib1{at}sanger.ac.uk.

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 × 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.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received June 22, 2009.
    • Accepted December 10, 2009.
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  1. Diabetes vol. 59 no. 3 741-746
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