We completed genotyping subjects with both the Affymetrix 100,000 SNP chip and the 1 million SNP chip technologies. 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. Measures of BMI were available on all samples from Phase 1 and Phase 2. SNPs that provided the best associations for diabetes and/or a pre-diabetic trait (including BMI) were selected for additional genotyping in a population-based sample of 3501 full-heritage Pima Indians. This genotyping utilized a new high throughput technology (Bead Express). We recently completed genotyping the best signals from our genome-wide association analysis in a sample of 3501 full hertiage Pima Indians and are currently replicating the best SNPs from this sample in a second population-based sample of 3784 mixed heritage Native Americans. To date the strongest assocations in the combined samples for diabetes are with SNPs in DNER (P= 1 x 10-8) and with KCNQ1 (P= 5 x 10-9). The strongest associations in the combined samples for BMI are with SNPs in BRD2, HEATR5B, UBE2E, GSTA5, NOVA1, FTO, MAP2K3, and CYB5A (all P between 10-6 and 10-7). Studies are ongoing to identify the casual variant that underlies each of these associations.
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|Hanson, Robert L; Guo, Tingwei; Muller, Yunhua L et al. (2013) Strong Parent-of-Origin Effects in the Association of KCNQ1 Variants With Type 2 Diabetes in American Indians. Diabetes 62:2984-91|
|Bian, Li; Traurig, Michael; Hanson, Robert L et al. (2013) MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation. Hum Mol Genet :|
|Malhotra, Alka; Kobes, Sayuko; Knowler, William C et al. (2011) A genome-wide association study of BMI in American Indians. Obesity (Silver Spring) 19:2102-6|
|Ma, Lijun; Hanson, Robert L; Traurig, Michael T et al. (2010) Evaluation of A2BP1 as an obesity gene. Diabetes 59:2837-45|