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

Abstract

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. Design and 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-hour 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 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 risk for T2D in American Indians.

The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders

“…Compared to large outbred populations, isolated populations show extended patterns of linkage disequilibrium (LD), and a higher probability for the presence of disease-associated variants with high frequency due to genetic drift and selection [3,4]. These properties are advantageous for genetic-association studies, which have recently been demonstrated in various isolated populations by the discovery of novel variants associated with cardio-metabolic traits [5][6][7][8][9][10][11][12][13], and of particular interest coding variants in CREBRF and ADCY3 have been associated with obesity in Samoans and Greenlanders, respectively [14,15].…”

RING finger protein 10 attenuates vascular restenosis by inhibiting vascular smooth muscle cell hyperproliferation in vivo and vitro

“…Meanwhile, there is a positive linkage between RNF10 and MetS. In addition, RNF10 has been found to be significantly enhanced in obesity and diabetes, contributing to disorders of glucose and lipid metabolism (9). Moreover, RNF10 is shown to repress cell proliferation (10).…”

Cross-Tissue and Tissue-Specific eQTLs: Partitioning the Heritability of a Complex Trait

“…Consequently, a number of large-scale exome and whole-genome sequencing efforts to identify such rare variants underlying T2D risk within specific populations are ongoing. 25,26 Alternatively, the majority of ''missing'' heritability might instead be ''hidden'' and explained by the cumulative effect of many variants with small effect sizes. [27][28][29][30] Recently, investigators have tested this hypothesis by applying linear mixed models (LMMs), which treat individual SNP effects as random effects and allow for the estimation of total additive genetic variance.…”