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Identification of Novel Candidate Genes for Type 2 Diabetes From a Genome-Wide Association Scan in the Old Order Amish

Evidence for Replication From Diabetes-Related Quantitative Traits and From Independent Populations

¹ Division of Endocrinology, Diabetes and Nutrition, University of Maryland, Baltimore, Maryland
² Geriatric Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland

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

Abbreviations: AFDS, Amish Family Diabetes Study; DGI, Broad-Lund-Novartis Diabetes Genome Initiative; GAUC, glucose area under the curve; GWAS, genome-wide association scan; HOMA-IR, homeostasis model assessment of insulin resistance; IAUC, insulin area under the curve; ISI, insulinogenic index; LD, linkage disequilibrium; NGT, normal glucose tolerant; OGTT, oral glucose tolerance test; SNP, single nucleotide polymorphism

OBJECTIVE— We sought to identify type 2 diabetes susceptibility genes through a genome-wide association scan (GWAS) in the Amish.

RESEARCH DESIGN AND METHODS— DNA from 124 type 2 diabetic case subjects and 295 control subjects with normal glucose tolerance were genotyped on the Affymetrix 100K single nucleotide polymorphism (SNP) array. A total of 82,485 SNPs were tested for association with type 2 diabetes. Type 2 diabetes–associated SNPs were further prioritized by the following: 1) associations with 5 oral glucose tolerance test (OGTT) traits in 427 nondiabetic Amish subjects, and 2) in silico replication from three independent 100L SNP GWASs (Framingham Heart Study Caucasians, Pima Indians, and Mexican Americans) and a 500K GWAS in Scandinavians.

RESULTS— The strongest association (P = 1.07 x 10^–5) was for rs2237457, which is located in growth factor receptor–bound protein 10 (Grb10), an adaptor protein that regulate insulin receptor signaling. rs2237457 was also strongly associated with OGTT glucose area under the curve in nondiabetic subjects (P = 0.001). Of the 1,093 SNPs associated with type 2 diabetes at P < 0.01, 67 SNPs demonstrated associations with at least one OGTT trait in nondiabetic individuals; 80 SNPs were nominally associated with type 2 diabetes in one of the three independent 100K GWASs, 3 SNPs (rs2540317 in MFSD9, rs10515353 on chromosome 5, and rs2242400 in BCAT1 were associated with type 2 diabetes in more than one population), and 11 SNPs were nominally associated with type 2 diabetes in Scandinavians. One type 2 diabetes–associated SNP (rs3845971, located in FHIT) showed replication with OGTT traits and also in another population.

CONCLUSIONS— Our GWAS of type 2 diabetes identified several gene variants associated with type 2 diabetes, some of which are worthy of further study.

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