A Genome-Wide Association Study in American Indians Implicates DNER as a Susceptibility Locus for Type 2 Diabetes

Most genetic variants associated with type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWASs) in Europeans. The present study reports a GWAS for young-onset T2DM in American Indians. Participants were selected from a longitudinal study conducted in Pima Indians and included: 278 cases with diabetes with onset before 25 years of age, 295 nondiabetic controls ≥age 45 years and 267 siblings of cases or controls. Individuals were genotyped on a ∼1M single nucleotide polymorphism (SNP) array, resulting in 453,654 SNPs with minor allele frequency >0.05. SNPs were analyzed for association in cases and controls and a family-based association test was conducted. Tag SNPs (n=311) were selected for 499 SNPs associated with diabetes (p<0.0005 in case-control analyses or p<0.0003 in family-based analyses), and these SNPs were genotyped in up to 6834 additional Pima Indians to assess replication. Rs1861612 in DNER was associated with T2DM (odds ratio=1.29 per copy of the T allele, p=6.6x10-8, which represents genome-wide significance accounting for the number of effectively independent SNPs analyzed). Transfection studies in murine pancreatic β-cells suggested that DNER regulates expression of notch signaling pathway genes. These studies implicate DNER as a susceptibility gene for T2DM in American Indians.