A genome-wide association study in American Indians implicates DNER as a susceptibility locus for type 2 diabetes

Robert L. Hanson, Yunhua L. Muller, Sayuko Kobes, Tingwei Guo, Li Bian, Victoria Ossowski, Kim Wiedrich, Jeffrey Sutherland, Christopher Wiedrich, Darin Mahkee, Ke Huang, Maryam Abdussamad, Michael Traurig, E. Jennifer Weil, Robert G. Nelson, Peter H. Bennett, William C. Knowler, Clifton Bogardus, Leslie J. Baier

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39 Scopus citations

Abstract

Most genetic variants associated with type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWASs) in Europeans. The current 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 ≥45 years of age, 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 6,834 additional Pima Indians to assess replication. Rs1861612 in DNER was associated with T2DM (odds ratio = 1.29 per copy of the T allele; P = 6.6 × 10-8, 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.

Original languageEnglish (US)
Pages (from-to)369-376
Number of pages8
JournalDiabetes
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2014

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Hanson, R. L., Muller, Y. L., Kobes, S., Guo, T., Bian, L., Ossowski, V., Wiedrich, K., Sutherland, J., Wiedrich, C., Mahkee, D., Huang, K., Abdussamad, M., Traurig, M., Weil, E. J., Nelson, R. G., Bennett, P. H., Knowler, W. C., Bogardus, C., & Baier, L. J. (2014). A genome-wide association study in American Indians implicates DNER as a susceptibility locus for type 2 diabetes. Diabetes, 63(1), 369-376. https://doi.org/10.2337/db13-0416