Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Abstract

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.

Figure 1

Regional plots of six confirmed associations. For each of the (A) JAZF1, (B) CDC123/CAMK1D, (C) TSPAN8/LGR5, (D) THADA, (E) ADAMTS9 and (F) NOTCH2/ADAM30 regions, genotyped and imputed SNPs passing QC across all three stage 1 studies are plotted with their meta-analysis p values (as −log10 values) as a function of genomic position (with NCBI Build 35). In each panel, the SNP taken forward to stages 2 and 3 is represented by a blue diamond (meta-analysis p value across stages 1-3), and its initial p value in stage 1 data is denoted by a red diamond. Estimated recombination rates (taken from HapMap) are plotted to reflect the local LD structure around the associated SNPs and their correlated proxies (according to a white to red scale from r²=0 to r²=1; based on pairwise r² values from HapMap CEU). Gene annotations were taken from the University of California-Santa Cruz genome browser.