Whole exome sequencing identifies variation in CYB5A and RNF10 associated with adiposity and type 2 diabetes

Objective Few coding variants in genes associated with type 2 diabetes (T2D) have been identified, and the underlying physiologic mechanisms whereby susceptibility genes influence T2D risk are often unknown. The objective of this study was to identify coding variation that increases risk for T2D via an effect on a pre‐diabetic trait. Methods Whole exome sequencing was done in 177 Pima Indians. Selected variants (N = 345) were genotyped in 555 subjects characterized for body fatness, glucose disposal rates during a clamp, acute insulin response to glucose, and 2‐h plasma glucose concentrations during an OGTT, and were also genotyped in up to 5,880 subjects with longitudinal measures of BMI. Variants associated with quantitative traits were assessed for association with T2D in 7,667 subjects. Results rs7238987 in CYB5A associated with body fatness (P = 7.0 × 10−6). This SNP and a novel SNP in RNF10 also associated with maximum recorded BMI (P = 6.2 × 10−7 and P = 7.2 × 10−4) and maximum childhood BMI z‐score (P = 5.9 × 10−4 and P = 8.5 × 10−7). The BMI increasing alleles increased the risk for T2D (P = 0.01; OR = 1.13 [1.03‐1.24] and 9.5 × 10−3; OR = 1.49 [1.10‐2.02]). Conclusions CYB5A, which has a role in stearyl‐CoA‐desaturase activity, and RNF10, with an unknown role in weight regulating pathways, associated with adiposity and nominally increased the risk for T2D in American Indians.