结合蛋白质组学的大规模全基因组分析揭示了与身体虚弱相关的新基因座和生物学见解。

Large-scale genome-wide analyses with proteomics integration reveal novel loci and biological insights into frailty.

作者信息

Mak Jonathan K L, Qin Chenxi, Krüger Moritz, Kuukka Anna, Hägg Sara, Lin Jake, Jylhävä Juulia

机构信息

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

出版信息

Nat Aging. 2025 Aug;5(8):1589-1600. doi: 10.1038/s43587-025-00925-y. Epub 2025 Aug 5.

DOI:10.1038/s43587-025-00925-y

PMID:40764432

Abstract

Frailty is a clinically relevant phenotype with notable gaps in our understanding of its etiology. Using the Hospital Frailty Risk Score (HFRS) to define frailty, we performed a genome-wide association study in FinnGen (N = 500,737), replicated the results in the UK Biobank (N = 407,463) and performed a meta-analysis. We prioritized genes through colocalization with expression, splicing and protein quantitative trait loci and proteomics integration. We identified 53 independent lead variants associated with frailty (P < 5 × 10), of which 45 were novel and not previously reported in the GWAS Catalog. Replication at the individual variant and polygenic risk score of the HFRS (P = 1.86 × 10) levels and meta-analysis largely confirmed the findings. Colocalization analysis supported a causal role for several genes, including CHST9, C6orf106 (ILRUN), KHK, MET, APOE, CGREF1 and PPP6C. Additionally, plasma levels of MET, CGREF1 and APOE were associated with HFRS. Our results reveal new genetic contributions to frailty and shed light on its biological basis.

摘要

衰弱是一种具有临床相关性的表型，我们对其病因的理解存在显著差距。我们使用医院衰弱风险评分（HFRS）来定义衰弱，在芬兰基因数据库（N = 500,737）中进行了全基因组关联研究，在英国生物银行（N = 407,463）中重复了研究结果，并进行了荟萃分析。我们通过与表达、剪接和蛋白质数量性状位点以及蛋白质组学整合的共定位来确定基因优先级。我们鉴定出53个与衰弱相关的独立先导变异（P < 5 × 10），其中45个是新的，之前未在全基因组关联研究目录中报道。在HFRS的个体变异和多基因风险评分（P = 1.86 × 10）水平上的重复研究和荟萃分析在很大程度上证实了这些发现。共定位分析支持了包括CHST9、C6orf106（ILRUN）、KHK、MET、APOE、CGREF1和PPP6C在内的几个基因的因果作用。此外，MET、CGREF1和APOE的血浆水平与HFRS相关。我们的结果揭示了衰弱新的遗传贡献，并阐明了其生物学基础。