Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes.
Todd JA., Walker NM., Cooper JD., Smyth DJ., Downes K., Plagnol V., Bailey R., Nejentsev S., Field SF., Payne F., Lowe CE., Szeszko JS., Hafler JP., Zeitels L., Yang JH., Vella A., Nutland S., Stevens HE., Schuilenburg H., Coleman G., Maisuria M., Meadows W., Smink LJ., Healy B., Burren OS., Lam AA., Ovington NR., Allen J., Adlem E., Leung HT., Wallace C., Howson JM., Guja C., Ionescu-Tîrgovişte C., Genetics of Type 1 Diabetes in Finland None., Simmonds MJ., Heward JM., Gough SC., Wellcome Trust Case Control Consortium None., Dunger DB., Wicker LS., Clayton DG.
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.