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

Abstract

Objective. Type 2 diabetes (T2D) is the result of complex interactions between genetic susceptibility and environmental factors.

Research Design and Methods. We performed a genome-wide association scan (GWAS) or T2D in the Amish; 93,087 SNPs were tested for association in 124 T2D cases and 295 normoglycemic controls. We tested the most strongly T2D-associated for association with oral glucose tolerance (OGTT) traits in 427 non-diabetic Amish individuals, and replication from GWAS from four independent populations (Caucasians from the Framingham Heart Study, Mexican Americans, Pima Indians, and Caucasians from Scandinavia).

Results. We identified 1,316 SNPs that were associated with T2D in the Amish (p<0.01). The strongest association (p=1.07 x 10^-5) was for rs2237457, which is located in intron 4 of growth factor receptor-bound protein 10 (GRB10), an adaptor protein known to regulate signaling of insulin receptors. Of the T2D-associated SNPs in the Amish, 65 unique SNPs demonstrated internal associations (p<0.01) with at least one of five OGTT traits in non-diabetic individuals. Genes notable for internal associations include ESRRG, FHIT, ADAM12, and C10orf59. In external comparisons, 73 unique SNPs were associated with T2D in the Amish and at least one other population. Among these, SNPs in SLC8A1 and BCAT1 were associated with T2D in the Amish and two other populations. Other genes of potential interest include GPC5, CSN3, INPP4B, LOC730727, and C1orf24.

Conclusions. The results of our 100K GWAS of T2D in the Amish identified a tractable number of novel candidate genes that warrant further investigation.