Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes

Abstract

The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up) <or= 1.35 x 10(-9); P(overall) <or= 1.15 x 10(-14)), leaving eight regions with small effects or false-positive associations. We also obtained evidence for chromosome 18q22 (P(overall) = 1.38 x 10(-8)) from a GWA study of nonsynonymous SNPs. Several regions, including 18q22 and 18p11, showed association with autoimmune thyroid disease. This study increases the number of T1D loci with compelling evidence from six to at least ten.

Figure 1

Odds ratios for the susceptibility allele for the ten independent type 1 diabetes associated genes or regions. The filled black bars indicate previously known associated genes and regions. The open bar indicates the IFIH1 region identified by the nsSNP genome scan (Table 2), and the filled gray bars were identified by the WTCCC Affymetrix 500K scan and confirmed by the studies reported here (Table 1). The HLA class II SNP (rs3129934) was the marker with the highest association with T1D in the MHC 25-35 Mb region in the WTCCC study.