Fine mapping of type 2 diabetes susceptibility loci

Abstract

Genome-wide association studies of type 2 diabetes have been extremely successful in discovering loci that contribute genetic effects to susceptibility to the disease. However, at the vast majority of these loci, the variants and transcripts through which these effects on type 2 diabetes are mediated are unknown, limiting progress in defining the pathophysiological basis of the disease. In this review, we will describe available approaches for assaying genetic variation across loci and discuss statistical methods to determine the most likely causal variants in the region. We will consider the utility of trans-ethnic meta-analysis for fine mapping by leveraging the differences in the structure of linkage disequilibrium between diverse populations. Finally, we will discuss progress in fine-mapping type 2 diabetes susceptibility loci to date and consider the prospects for future efforts to localise causal variants for the disease.

Fig. 1

Fine-mapping of the KCNQ1 locus. Each point represents a Metabochip SNP passing quality control in a meta-analysis of 34,840 T2D cases and 114,981 controls, primarily of European descent. Each SNP is plotted with their p value (on a −log₁₀ scale, y-axis) as a function of genomic position (NCBI Build 36, x-axis). The lead SNP (rs163184) is represented by the purple circle. The colour coding of all other SNPs indicates LD with the lead SNP (estimated by CEU r ² from the 1000 Genomes Project, June 2010 release): red r ² ≥ 0.8, gold 0.6 ≤ r ² < 0.8, green 0.4 ≤ r ² < 0.6, cyan 0.2 ≤ r ² < 0.4, blue r ² < 0.2, and grey r ² unknown. Recombination rates are estimated from the International HapMap Project and gene annotations are taken from the University of California Santa Cruz genome browser