美国哈佛大学和麻省理工学院布罗德研究所Josep M. Mercader及其研究团队，通过对51,256例2型糖尿病（T2D）患者和370,487名健康个体进行的罕见变异分析，揭示了单基因糖尿病基因的致病范围。相关论文于2024年10月8日发表在《自然—遗传学》杂志上。

据了解，由于以往计算的局限性和WGS数据的稀缺，2型糖尿病GWAS经常会忽略罕见变异。

研究人员利用TOPMed估算和全基因组测序（WGS）数据，进行了最大规模的T2D 全基因组关联研究（GWAS）分析，其中包含51,256例T2 病例和370,487健康个体，该分析旨在发现等位基因频率小于5 × 10^-5的变异。

研究发现了12个新变异，包括LEP基因附近一个罕见的在非洲/非裔美国人中富含的增强子变异（rs147287548），它与T2D风险增加具有四倍关系。研究还在HNF4A（p.Arg114Trp）中发现了一个罕见的错义变异，它增加了8倍的T2D发病风险。

研究人员进一步利用这些数据，分析了22个与单基因糖尿病相关基因中的1,634个ClinVar变异，在HNF1A和GCK中又发现了两个分别与T2D风险增加呈五倍和八倍相关的罕见变异，它们的影响随个体的多基因风险评分而改变。

在ClinVar中，有21%的变异具有相互矛盾的解释或不确定功能，研究根据它们与T2D缺乏的关联情况，证明它们是不具有致病性的。该工作为利用罕见变异GWAS鉴定大效应变异，和评估单基因糖尿病基因变异的致病性提供了一个模型。

附：英文原文

Title: Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes

Author: Huerta-Chagoya, Alicia, Schroeder, Philip, Mandla, Ravi, Li, Jiang, Morris, Lowri, Vora, Maheak, Alkanaq, Ahmed, Nagy, Dorka, Szczerbinski, Lukasz, Madsen, Jesper G. S., Bons-Guarch, Silvia, Mollandin, Fanny, Cole, Joanne B., Porneala, Bianca, Westerman, Kenneth, Li, Josephine H., Pollin, Toni I., Florez, Jose C., Gloyn, Anna L., Carey, David J., Cebola, Ins, Mirshahi, Uyenlinh L., Manning, Alisa K., Leong, Aaron, Udler, Miriam, Mercader, Josep M.

Issue&Volume: 2024-10-08

Abstract: 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 5×105. 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.

DOI: 10.1038/s41588-024-01947-9

Source: https://www.nature.com/articles/s41588-024-01947-9