Park Junyoung, Peña-Tauber Andrés, Talozzi Lia, Greicius Michael D, Le Guen Yann
Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA.
Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, 94304, USA.
Nat Commun. 2025 Feb 28;16(1):2064. doi: 10.1038/s41467-025-57315-6.
Human lifespan is shaped by genetic and environmental factors. To enable precision health, understanding how genetic variants influence mortality is essential. We conducted a survival analysis in European ancestry participants of the UK Biobank, using age-at-death (N=35,551) and last-known-age (N=358,282). The associations identified were predominantly driven by cancer. We found lifespan-associated loci (APOE, ZSCAN23) for common variants and six genes where burden of loss-of-function variants were linked to reduced lifespan (TET2, ATM, BRCA2, CKMT1B, BRCA1, ASXL1). Additionally, eight genes with pathogenic missense variants were associated with reduced lifespan (DNMT3A, SF3B1, TET2, PTEN, SOX21, TP53, SRSF2, RLIM). Many of these genes are involved in oncogenic pathways and clonal hematopoiesis. Our findings highlight the importance of understanding genetic factors driving the most prevalent causes of mortality at a population level, highlighting the potential of early genetic testing to identify germline and somatic variants increasing one's susceptibility to cancer and/or early death.
人类寿命受遗传和环境因素影响。为实现精准健康，了解基因变异如何影响死亡率至关重要。我们对英国生物银行中具有欧洲血统的参与者进行了生存分析，使用死亡年龄（N = 35,551）和最后已知年龄（N = 358,282）。所确定的关联主要由癌症驱动。我们发现了常见变异的寿命相关基因座（APOE、ZSCAN23）以及六个基因，其中功能丧失变异的负担与寿命缩短有关（TET2、ATM、BRCA2、CKMT1B、BRCA1、ASXL1）。此外，八个具有致病性错义变异的基因与寿命缩短有关（DNMT3A、SF3B1、TET2、PTEN、SOX21、TP53、SRSF2、RLIM）。这些基因中的许多都参与致癌途径和克隆性造血。我们的研究结果强调了在人群水平上了解驱动最普遍死亡原因的遗传因素的重要性，突出了早期基因检测在识别增加个体患癌和/或早死易感性的种系和体细胞变异方面的潜力。
