We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10⁻⁸) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4⁺ effector T cells. Using chromatin-accessibility profiling of CD4⁺ T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein–protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.

我们报告了迄今为止规模最大、最多样化的 1 型糖尿病 (T1D) 基因研究（61,427 名参与者），产生了 78 个全基因组显着 ( P < 5 × 10 ^-8 ) 区域，其中包括 36 个新区域。我们定义了可信的 T1D 相关变异集，并表明它们富含免疫细胞可及的染色质，特别是 CD4 ⁺效应 T 细胞。利用来自 115 个个体的 CD4 ⁺ T 细胞的染色质可及性分析，我们绘制了染色质可及性数量性状基因座，并确定了 T1D 风险变异与染色质可及性数量性状基因座共定位的五个区域。我们强调BACH2中的 rs72928038 作为候选因果 T1D 变异，导致 T 细胞中增强子可及性和BACH2表达降低。最后，我们通过整合遗传证据、功能基因组图谱和免疫蛋白-蛋白相互作用来确定潜在药物靶点的优先顺序，确定与 T1D 相关的 12 个基因，这些基因已成为自身免疫性疾病临床试验的目标。这些发现为 T1D 提供了扩展的基因组图谱。