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 Preplication < 0.05 and Pcombined < Pdiscovery. In silico analysis prioritized a rare variant at 2q24.3 (rs60587303 [C], MAF 0.5%) within the first intron of STK39, with an effect size comparable with those of common variants in the INS and PTPN22 loci (combined [from the discovery and replication cohorts] estimate of odds ratio [ORcombined] 1.97, 95% CI 1.58–2.47, Pcombined = 2.9 × 10−9). Pharmacological inhibition of Stk39 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.

中文翻译：

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影响 1 型糖尿病风险的罕见遗传变异。

大多数 1 型糖尿病的复制遗传决定因素是常见的（次要等位基因频率 [MAF] > 5%）。我们旨在鉴定对 1 型糖尿病风险有重大影响的新型罕见或低频 (MAF <5%) 单核苷酸多态性。我们对基因分型数据进行了深度插补，然后对来自 12 个欧洲队列的 9,358 名 1 型糖尿病病例和 15,705 名对照受试者进行了全基因组关联测试和荟萃分析。在由 4,329 名病例和 9,543 名对照受试者组成的单独队列中复制了候选变体。我们的荟萃分析确定了 MHC 之外的 27 个独立变异，其中 3 个是新的并且 MAF <5%。其中三个变体以 Preplication < 0.05 和 Pcombined < Pdiscovery 进行复制。计算机分析优先考虑 2q24.3 (rs60587303 [C], MAF 0. 5%) 在 STK39 的第一个内含子内，其效应大小与 INS 和 PTPN22 基因座中常见变异的效应相当（结合 [来自发现和复制队列] 比值比估计 [OR 组合] 1.97，95% CI 1.58– 2.47，Pcombined = 2.9 × 10−9）。在原代鼠 T 细胞中对 Stk39 活性的药理学抑制通过增强白细胞介素 2 信号增强效应反应。这些发现提供了对 1 型糖尿病遗传结构的洞察，并确定了对疾病风险有很大影响的罕见变异。在原代鼠 T 细胞中对 Stk39 活性的药理学抑制通过增强白细胞介素 2 信号增强效应反应。这些发现提供了对 1 型糖尿病遗传结构的洞察，并确定了对疾病风险有很大影响的罕见变异。在原代鼠 T 细胞中对 Stk39 活性的药理学抑制通过增强白细胞介素 2 信号增强效应反应。这些发现提供了对 1 型糖尿病遗传结构的洞察，并确定了对疾病风险有很大影响的罕见变异。