Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes.

Abstract

Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency [MAF] >5%). We aimed to identify novel rare or low-frequency (MAF <5%) single nucleotide polymorphisms with large effects on risk of type 1 diabetes. We undertook deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 type 1 diabetes case and 15,705 control subjects from 12 European cohorts. Candidate variants were replicated in a separate cohort of 4,329 case and 9,543 control subjects. Our meta-analysis identified 27 independent variants outside the MHC, among which 3 were novel and had MAF <5%. Three of these variants replicated with <i>P</i> _replication < 0.05 and <i>P</i> _combined < <i>P</i> _discovery In silico analysis prioritized a rare variant at 2q24.3 (rs60587303 [C], MAF 0.5%) within the first intron of <i>STK39,</i> with an effect size comparable with those of common variants in the <i>INS</i> and <i>PTPN22</i> loci (combined [from the discovery and replication cohorts] estimate of odds ratio [OR_combined] 1.97, 95% CI 1.58-2.47, <i>P</i> _combined = 2.9 × 10^-9). Pharmacological inhibition of <i>Stk39</i> activity in primary murine T cells augmented effector responses through enhancement of interleukin 2 signaling. These findings provide insight into the genetic architecture of type 1 diabetes and have identified rare variants having a large effect on disease risk.