Linkage Disequilibrium Mapping of the Replicated Type 2 Diabetes Linkage Signal on Chromosome 1q

  1. Inga Prokopenko1,2,
  2. Eleftheria Zeggini1,3,
  3. Robert L. Hanson4,
  4. Braxton D. Mitchell5,
  5. N. William Rayner1,2,
  6. Pelin Akan3,
  7. Leslie Baier4,
  8. Swapan K. Das6,7,
  9. Katherine S. Elliott1,
  10. Mao Fu5,
  11. Timothy M. Frayling8,
  12. Christopher J. Groves1,2,
  13. Rhian Gwilliam3,
  14. Laura J. Scott9,
  15. Benjamin F. Voight10111213,
  16. Andrew T. Hattersley8,
  17. Cheng Hu14,
  18. Andrew D. Morris15,
  19. Maggie Ng16,
  20. Colin N.A. Palmer17,
  21. Marcela Tello-Ruiz18,
  22. Martine Vaxillaire19,
  23. Cong-rong Wang14,
  24. Lincoln Stein1820,
  25. Juliana Chan16,
  26. Weiping Jia14,
  27. Philippe Froguel1921,
  28. Steven C. Elbein6,
  29. Panos Deloukas3,
  30. Clifton Bogardus4,
  31. Alan R. Shuldiner5,
  32. Mark I. McCarthy1,2,22 and
  33. for the International Type 2 Diabetes 1q Consortium
  1. 1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K;
  2. 2Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.;
  3. 3Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, U.K.;
  4. 4Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona;
  5. 5School of Medicine, University of Maryland, Baltimore, Maryland;
  6. 6Endocrinology Section, Medical Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas;
  7. 7Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas;
  8. 8Institute of Clinical and Biomedical Science, Peninsula Medical School, Exeter, U.K.;
  9. 9Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan;
  10. 10Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts;
  11. 11Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts;
  12. 12Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts;
  13. 13Department of Medicine, Harvard Medical School, Boston, Massachusetts;
  14. 14Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Jiaotong University No. 6 People's Hospital, Shanghai, China;
  15. 15Diabetes Research Group, Biomedical Research Institute, University of Dundee, Dundee, U.K.;
  16. 16Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong, SAR;
  17. 17Biomedical Research Institute, Ninewells Hospital and Medical School, Dundee, U.K.;
  18. 18Cold Spring Harbor Laboratory, New York, New York;
  19. 19CNRS UMR 8090, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France;
  20. 20Informatics & Biocomputing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
  21. 21Genomic Medicine, Hammersmith Hospital, Imperial College London, London, U.K.;
  22. 22Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
  1. Corresponding author: Mark McCarthy, mark.mccarthy{at}drl.ox.ac.uk.
  1. I.P. and E.Z. contributed equally to this work.

Abstract

OBJECTIVE Linkage of the chromosome 1q21–25 region to type 2 diabetes has been demonstrated in multiple ethnic groups. We performed common variant fine-mapping across a 23-Mb interval in a multiethnic sample to search for variants responsible for this linkage signal.

RESEARCH DESIGN AND METHODS In all, 5,290 single nucleotide polymorphisms (SNPs) were successfully genotyped in 3,179 type 2 diabetes case and control subjects from eight populations with evidence of 1q linkage. Samples were ascertained using strategies designed to enhance power to detect variants causal for 1q linkage. After imputation, we estimate ∼80% coverage of common variation across the region (r 2 > 0.8, Europeans). Association signals of interest were evaluated through in silico replication and de novo genotyping in ∼8,500 case subjects and 12,400 control subjects.

RESULTS Association mapping of the 23-Mb region identified two strong signals, both of which were restricted to the subset of European-descent samples. The first mapped to the NOS1AP (CAPON) gene region (lead SNP: rs7538490, odds ratio 1.38 [95% CI 1.21–1.57], P = 1.4 × 10−6, in 999 case subjects and 1,190 control subjects); the second mapped within an extensive region of linkage disequilibrium that includes the ASH1L and PKLR genes (lead SNP: rs11264371, odds ratio 1.48 [1.18–1.76], P = 1.0 × 10−5, under a dominant model). However, there was no evidence for association at either signal on replication, and, across all data (>24,000 subjects), there was no indication that these variants were causally related to type 2 diabetes status.

CONCLUSIONS Detailed fine-mapping of the 23-Mb region of replicated linkage has failed to identify common variant signals contributing to the observed signal. Future studies should focus on identification of causal alleles of lower frequency and higher penetrance.

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 January 18, 2009.
    • Accepted April 1, 2009.
  • 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.

| Table of Contents

This Article

  1. Diabetes vol. 58 no. 7 1704-1709
  1. Online-Only Appendix
  2. All Versions of this Article:
    1. db09-0081v1
    2. 58/7/1704 most recent