A Dense (1 Million SNP) Genome-Wide Association Study in Pima Indians

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

We recently completed genotyping subjects with the Affymetrix 1 Million SNP chip technology. Phase 1 was designed to detect potential associations with young-onset type 2 diabetes, by genotyping 300 early-onset type 2 diabetes subjects (onset age<25 yrs) and 329 non-diabetic controls (age >45 yrs), and 271 additional subjects who were diabetic and non-diabetic siblings of the selected subjects. Associations with diabetes were calculated using both a case/control analysis (N= 629) and a within-family analysis (482 siblings from 169 sibships), and SNPs that had the strongest association for the combined associations were prioritized. Phase 2 of the GWA was designed to detect associations with pre-diabetic traits (% body fat, insulin action as measured by the hyperinsulinemic euglycemic clamp technique, and the acute insulin response to an intravenous bolus of glucose). Six hundred non-diabetic subjects who had been metabolically phenotyped for these predictors of diabetes were genotyped using the 1 Million SNP chip. SNPs that provided the best associations for diabetes and/or a pre-diabetic trait were selected for additional genotyping in a population-based sample of 3501 full-heritage Pima Indians. This genotyping is ongoing using a new high throughput technology (Bead Express). We are also comparing our 1 Million SNP GWAS results with those obtained in other populations such as the Chinese, to identify potential regions of overlap which may implicate genes that have notable effects across many populations.