Novel Common Variants Associated with Obesity and Type 2 Diabetes Detected Using a cFDR Method

Abstract

Genome-wide association studies (GWASs) have been performed extensively in diverse populations to identify single nucleotide polymorphisms (SNPs) associated with complex diseases or traits. However, to date, the SNPs identified fail to explain a large proportion of the variance of the traits/diseases. GWASs on type 2 diabetes (T2D) and obesity are generally focused on individual traits independently, and genetic intercommunity (common genetic contributions or the product of over correlated phenotypic world) between them are largely unknown, despite extensive data showing that these two phenotypes share both genetic and environmental risk factors. Here, we applied a recently developed genetic pleiotropic conditional false discovery rate (cFDR) approach to discover novel loci associated with BMI and T2D by incorporating the summary statistics from existing GWASs of these two traits. Conditional Q-Q and fold enrichment plots were used to visually demonstrate the strength of pleiotropic enrichment. Adopting a cFDR nominal significance level of 0.05, 287 loci were identified for BMI and 75 loci for T2D, 23 of which for both traits. By incorporating related traits into a conditional analysis framework, we observed significant pleiotropic enrichment between obesity and T2D. These findings may provide novel insights into the etiology of obesity and T2D, individually and jointly.

Leveraging epigenomics and contactomics data to investigate SNP pairs in GWAS

“…The pair (rs2789686, rs74145425), identified in the adipose tissue analyses, is annotated to the promoter of ANXA11 , which is one of 3 novel genes recently associated to T2D (Zhang et al 2017). There are also 2 pairs, both involving the SNP rs2789686 and a SNP in the promoter of PLAC9 that were identified in these analyses.…”

Additional common variants associated with type 2 diabetes and coronary artery disease detected using a pleiotropic cFDR method

“…The cFDR approach is well-established now and has been widely applied by many other groups 4,7,8,28,29 and our group. 12–14,30 We briefly summarize this cFDR approach as follows: after the data preparation processing as indicated in the previous papers, we computed the conditional empirical cumulative distribution functions (cdfs) of the corrected p-values for the x axis in conditional QQplot. Empirical cdfs for T2D SNP p-values were conditioned on nominal p-values in CARD, and vice versa.…”

Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective

“…In a group of 137 morbidly obese patients who had biliopancreatic diversion, GG genotype carriers of the rs6923761 showed higher weight loss after bariatric surgery at 12 and 18 months [ 166 ]. In addition, the rs2268641 (C>T) SNP of GLP1R was associated with obesity in European Americans [ 158 ], and GIPR SNP rs2334255 (G>T) was identified as a novel common variant associated with both obesity and T2DM risk [ 167 ]. An analysis of the coding variants associated with BMI, which included data from 125 studies (718,734 individuals), found two single-nucleotide variants of GIPR that contribute independently to lower body weight.…”