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