Detection of novel obesity loci in Asian populations

Abstract

Genome-wide association studies (GWAS) have successfully identified common obesity-associated variants. These have been primarily conducted using populations of European ancestry and the relevance of these loci in other populations remains to be determined. The aims of this study were multi-fold, in both corroborating the role of these variants in Asians and in unravelling new obesity-associated variants. In my first study, I examined the relevance of specific variants, initially identified in Europeans, with obesity in Asian populations from Singapore (Chinese, Malays and South-Asians). This confirmed the role of several novel obesity loci and suggested that common variants obesity-associated variants were relevant across ethnic groups. To identify additional obesity-associated loci in East-Asians, a hypothesis-free GWAS approach was adopted in the next study. These studies were initially carried out in Singaporean datasets and subsequently, expanded to consortia levels to increase power in the study. These efforts successfully identified novel BMI-associated variants in East-Asians and highlighted that insulin-associated processes may be involved in obesity susceptibility. In the third study I extended the findings of a possible role for insulin-associated processes in obesity by aiming to understand the relevance of type 2 diabetes risk loci with obesity predisposition in adults and in childhood and birth among East-Asian datasets. Data from this study revealed a possible ethnic-specific association at a HHEX locus among adult East-Asians and identified another HHEX variant at which the effects on childhood BMI interacted with birth weight. In the final study, I assessed an inflammatory phenotype, serum C-reactive protein levels, for novel associations in East-Asian datasets using GWAS with a focus on identifying any obesity interactions. I further sought to clarify on the causality between CRP with vascular disease in this study. Although no novel variants were detected in this study, several initial findings from earlier GWAS were replicated in the East-Asian populations. Furthermore, it was determined that CRP was not causally associated with macrovascular and microvascular disease. Primary results from these studies served to replicate several novel obesity loci in Asian populations and revealed novel risk variants. Nevertheless, it is striking that much of the genetic variation in obesity levels remains unidentified. Additional research is necessary to pin-point causal location and mechanisms for the already identified loci and it would be important to address the role of non-SNP genetic variations in obesity susceptibility.