Estabilishing the Genetic Etiology in common human phenotypes

Abstract

It has been increasingly valuable to look across populations of different ancestries, taking advantage of the allelic frequency and linkage disequilibrium differences that could shed more light on the genetic architecture of common diseases and complex traits. Singapore is a small country state at the tip of the Malaysia Peninsula, home to a population of 5 million. The unique demographic makeup of the three main ethnic groups, Chinese, Malays and Asian Indians, captures much of the genetic diversity across Asia. We first assembled a resource of 100 individuals from each of the three ethnic groups, with the aim of comparing their genetic diversity within ethnic groups and also with existing HapMap populations to determine if this genetic diversity might have implications for genetic association studies. The multi-ethnic demographic characteristic allowed us to investigate various aims: (i) to identify disease susceptibility genetic loci common to multiple ethnic groups; (ii) to assess the impact of allele frequencies differences and allelic heterogeneity on the transferability of European loci to non-Europeans; (iii) to identify population specific disease implicated loci in genetic association studies. In particular, we will describe findings from a Type 2 Diabetes genome-wide association study that highlight the transferability and consistency of established Type 2 Diabetes loci from European populations to Asian populations. Through meta-analysis with other South Asian populations, we report six new loci implicated in Type 2 Diabetes in South Asian Indians. Finally, using the same ethnic groups, we demonstrate that re-defining phenotype has an important role in improving existing knowledge of disease pathogenesis and complementing our physiological understanding of genetic susceptible variants.