Genome-Wide and Fine-Mapping Linkage Studies of Type 2 Diabetes and Glucose Traits in the Old Order Amish

Evidence for a New Diabetes Locus on Chromosome 14q11 and Confirmation of a Locus on Chromosome 1q21-q24

  1. Wen-Chi Hsueh1,
  2. Pamela L. St. Jean2,
  3. Braxton D. Mitchell3,
  4. Toni I. Pollin3,
  5. William C. Knowler4,
  6. Margaret G. Ehm2,
  7. Callum J. Bell5,
  8. Hakan Sakul5,
  9. Michael J. Wagner2,
  10. Daniel K. Burns2 and
  11. Alan R. Shuldiner36
  1. 1Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas
  2. 2GlaxoSmithKline, Research Triangle Park, North Carolina
  3. 3Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
  4. 4National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
  5. 5Axys Pharmaceuticals, La Jolla, California
  6. 6Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland

    Abstract

    We conducted a genome scan using a 10-cM map to search for genes linked to type 2 diabetes in 691 individuals from a founder population, the Old Order Amish. We then saturated two regions on chromosomes 1 and 14 showing promising linkage signals with additional markers to produce a ∼2-cM map for fine mapping. Analyses of both discrete traits (type 2 diabetes and the composite trait of type 2 diabetes and/or impaired glucose homeostasis [IGH]), and quantitative traits (glucose levels during a 75-g oral glucose challenge, designated glucose 0–180 and HbA1c) were performed. We obtained significant evidence for linkage to type 2 diabetes in a novel region on chromosome 14q11 (logarithm of odds [LOD] for diabetes = 3.48, P = 0.00005). Furthermore, we observed evidence for the existence of a diabetes-related locus on chromosome 1q21-q24 (LOD for type 2 diabetes/IGH = 2.35, P = 0.0008), a region shown to be linked to diabetes in several other studies. Suggestive evidence for linkage to glucose traits was observed on three other regions: 14q11-q13 (telomeric to that above with LOD = 1.82–1.85 for glucose 150 and 180), 1p31 (LOD = 1.28–2.30 for type 2 diabetes and glucose 120–180), and 18p (LOD = 3.07, P = 0.000085 for HbA1c and LOD = 1.50 for glucose 0). In conclusion, our findings provide evidence that type 2 diabetes susceptibility genes reside on chromosomes 1, 14, and 18.

    Footnotes

    • Address correspondence and reprint requests to Alan R. Shuldiner, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 660 W. Redwood St., Room 494, Baltimore, MD 21201. E-mail: ashuldin{at}medicine.umaryland.edu.

      Received for publication 3 July 2002 and accepted in revised form 6 November 2002.

      W.-C.H. and P.L.S. contributed equally to this study.

      W.-C.H. is currently located at the University of California San Francisco School of Medicine, San Francisco, California; C.J.B. at EmerGen, Salt Lake City, Utah; and H.S. at Pfizer, Groton, Connecticut.

      P.L.S., M.G.E., M.J.W., and D.K.B. are employed by and hold stock in GlaxoSmithKline; C.J.B holds stock in Celera; and H.S. is employed by and holds stock in Pfizer.

      Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.

      AFDS, Amish Family Diabetes Study; AUC, area under the curve; IGH, impaired glucose homeostasis; LOD, logarithm of odds; LRT, likelihood ratio test; OGTT, oral glucose tolerance test; STR, short tandem repeat.

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