Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

Abstract

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.

Figure 1

Distribution of Z-scores from the Stage 2 meta-analysis, aligned to the risk allele from Stage 1. Z-scores were calculated at a subset of 3,412 independent T2D replication SNPs (CEU r² < 0.05), excluding the 63 established and newly discovered autosomal susceptibility loci represented on Metabochip. The Z-score distribution is a mixture of: (i) the “null distribution” of SNPs having no effect on T2D (blue curve); and (ii) the “alternative distribution” of SNPs associated with the disease (red curve).

Figure 2

Regional plots of T2D susceptibility loci with evidence of multiple association signals. Each point represents a Metabochip SNP passing quality control in our combined meta-analysis, plotted with their P-value (on a -log₁₀ scale) as a function of genomic position (NCBI Build 36). In each panel, the lead SNP is represented by the purple diamond. The color coding of all other SNPs (circles) indicates LD with the lead SNP (estimated by CEU r² from the 1000 Genomes Project June 2010 release): red r² ≥ 0.8; gold 0.6 ≤ r² < 0.8; green 0.4 ≤ r² < 0.6; cyan 0.2 ≤ r² < 0.4; blue r² < 0.2; grey r² unknown. Recombination rates are estimated from the International HapMap Project and gene annotations are taken from the University of California Santa Cruz genome browser.

Figure 3

Functional analyses. (a,b) Protein-protein interaction (PPI) sub-network for CREBBP and adipocytokine interactions. All direct interactions and common interactors between direct connections were extracted from the larger network of 314 proteins defined in the DAPPLE network analysis. Genes in the network are circles (nodes), colored according to the statistical relationship with T2D: common interactors between GWAS identified or monogenic loci are depicted as grey, monogenic loci (only) in blue, GWAS identified loci (only) in red, and loci with GWAS association and implicated by monogenic forms of diabetes are shown in green. Each interaction defined in the inWEB network is depicted by a line (edge) between nodes. (c) GRAIL circle plot of locus connectivity. Each locus is plotted in a circle where significant connections (P < 0.05) based on PubMed abstracts are drawn spanning the circle. Conservatively, we treated all monogenic loci (region 142) as a single locus by which connectivity is assessed. The strongest connections (P < 0.001) are colored in bright red. (d) GSEA of associations in the adipocytokine signaling pathway. The black bars represent the Stage 1 meta-analysis P-values of 63 autosomal genes in the Adipocytokine Signaling pathways (KEGG). A density plot of the black bars is depicted in the top panel (red line). The replicating genes in the leading edge of the GSEA are listed. The Stage 2 modified GSEA P = 1.6×10⁻⁴ was calculated based on both the primary and secondary transcripts using the LD locus definition.