Chapter I. Pathogenesis and Function

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Rev Diabet Stud, 2015, 12(3-4):299-319 DOI 10.1900/RDS.2015.12.299

Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?

Anup K. Nair, Leslie J. Baier

Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85004, USA

Manuscript submitted August 18, 2015; resubmitted October 16, 2015; accepted October 27, 2015.

Keywords: type 2 diabetes, GWAS, imputation, SNP, meta-analysis, ethnic group, functional variant, risk


Genetic studies in large outbred populations have documented a complex, highly polygenic basis for type 2 diabetes (T2D). Most of the variants currently known to be associated with T2D risk have been identified in large studies that included tens of thousands of individuals who are representative of a single major ethnic group such as European, Asian, or African. However, most of these variants have only modest effects on the risk for T2D; identification of definitive 'causal variant' or 'causative loci' is typically lacking. Studies in isolated populations offer several advantages over outbred populations despite being, on average, much smaller in sample size. For example, reduced genetic variability, enrichment of rare variants, and a more uniform environment and lifestyle, which are hallmarks of isolated populations, can reduce the complexity of identifying disease-associated genes. To date, studies in isolated populations have provided valuable insight into the genetic basis of T2D by providing both a deeper understanding of previously identified T2D-associated variants (e.g. demonstrating that variants in KCNQ1 have a strong parent-of-origin effect) or providing novel variants (e.g. ABCC8 in Pima Indians, TBC1D4 in the Greenlandic population, HNF1A in Canadian Oji-Cree). This review summarizes advancements in genetic studies of T2D in outbred and isolated populations, and provides information on whether the difference in the prevalence of T2D in different populations (Pima Indians vs. non-Hispanic Whites and non-Hispanic Whites vs. non-Hispanic Blacks) can be explained by the difference in risk allele frequencies of established T2D variants.

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