Type 2 diabetes (T2D) genome-wide association studies (GWASs) often overlook rare variants as a result of previous imputation panels’ limitations and scarce whole-genome sequencing (WGS) data. We used TOPMed imputation and WGS to conduct the largest T2D GWAS meta-analysis involving 51,256 cases of T2D and 370,487 controls, targeting variants with a minor allele frequency as low as 5 × 10⁻⁵. We identified 12 new variants, including a rare African/African American-enriched enhancer variant near the LEP gene (rs147287548), associated with fourfold increased T2D risk. We also identified a rare missense variant in HNF4A (p.Arg114Trp), associated with eightfold increased T2D risk, previously reported in maturity-onset diabetes of the young with reduced penetrance, but observed here in a T2D GWAS. We further leveraged these data to analyze 1,634 ClinVar variants in 22 genes related to monogenic diabetes, identifying two additional rare variants in HNF1A and GCK associated with fivefold and eightfold increased T2D risk, respectively, the effects of which were modified by the individual’s polygenic risk score. For 21% of the variants with conflicting interpretations or uncertain significance in ClinVar, we provided support of being benign based on their lack of association with T2D. Our work provides a framework for using rare variant GWASs to identify large-effect variants and assess variant pathogenicity in monogenic diabetes genes.

2 型糖尿病 （T2D） 全基因组关联研究 （GWAS） 经常忽视罕见的变异，这是由于先前的插补面板的局限性和稀缺的全基因组测序 （WGS） 数据。我们使用 TOPMed 插补和 WGS 进行了最大的 T2D GWAS 荟萃分析，涉及 51,256 例 T2D 和 370,487 例对照，针对次要等位基因频率低至 5 × 10⁻⁵ 的变异。我们确定了 12 个新变异，包括 LEP 基因 （rs147287548） 附近一种罕见的非洲/非裔美国人富集增强子变异，与 T2D 风险增加 4 倍相关。我们还在 HNF4A （p.Arg114Trp） 中发现了一种罕见的错义变异，与 T2D 风险增加 8 倍相关，之前在外显率降低的年轻人成熟发病糖尿病中报道，但在 T2D GWAS 中观察到。我们进一步利用这些数据分析了与单基因糖尿病相关的 22 个基因中的 1,634 个 ClinVar 变异，确定了 HNF1A 和 GCK 中另外两个罕见变异，分别与 T2D 风险增加 5 倍和 8 倍相关，其影响受到个体多基因风险评分的改变。对于 ClinVar 中 21% 的解释冲突或意义不确定的变异，我们提供了良性的支持，因为它们与 T2D 缺乏关联。我们的工作为使用罕见变异 GWAS 来识别大效应变异和评估单基因糖尿病基因中的变异致病性提供了一个框架。