Integrated genetic analyses revealed novel human longevity loci and reduced risks of multiple diseases in a cohort study of 15,651 Chinese individuals

• Published in: Aging cell 2021-03, Vol.20 (3), p.e13323-n/a
• Main Authors: Liu, Xiaomin, Song, Zijun, Li, Yan, Yao, Yao, Fang, Mingyan, Bai, Chen, An, Peng, Chen, Huashuai, Chen, Zhihua, Tang, Biyao, Shen, Juan, Gao, Xiaotong, Zhang, Mingrong, Chen, Pengyu, Zhang, Tao, Jia, Huijue, Liu, Xiao, Hou, Yong, Yang, Huanming, Wang, Jian, Wang, Fudi, Xu, Xun, Min, Junxia, Nie, Chao, Zeng, Yi
• Format: Article
• Language: English
• Subjects: Age; Apolipoprotein E; Arthritis; Cardiovascular diseases; centenarians; Cohort analysis; Datasets; Diabetes mellitus (non-insulin dependent); Disease; Genes; Genetic analysis; Genetic markers; Genetics; Genotype & phenotype; Health aspects; human genetics; Life span; Linkage disequilibrium; Longevity; Medical research; Medicine, Experimental; Meiosis; Mortality; Oldest old people; Original; Original Paper; Population; Prediction models; Prognosis; Risk factors; Sex; sex difference; Sex differences; Type 2 diabetes; XPC protein
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13323

There is growing interest in studying the genetic contributions to longevity, but limited relevant genes have been identified. In this study, we performed a genetic association study of longevity in a total of 15,651 Chinese individuals. Novel longevity loci, BMPER (rs17169634; p = 7.91 × 10−15) and TMEM43/XPC (rs1043943; p = 3.59 × 10−8), were identified in a case–control analysis of 11,045 individuals. BRAF (rs1267601; p = 8.33 × 10−15) and BMPER (rs17169634; p = 1.45 × 10−10) were significantly associated with life expectancy in 12,664 individuals who had survival status records. Additional sex‐stratified analyses identified sex‐specific longevity genes. Notably, sex‐differential associations were identified in two linkage disequilibrium blocks in the TOMM40/APOE region, indicating potential differences during meiosis between males and females. Moreover, polygenic risk scores and Mendelian randomization analyses revealed that longevity was genetically causally correlated with reduced risks of multiple diseases, such as type 2 diabetes, cardiovascular diseases, and arthritis. Finally, we incorporated genetic markers, disease status, and lifestyles to classify longevity or not‐longevity groups and predict life span. Our predictive models showed good performance (AUC = 0.86 for longevity classification and explained 19.8% variance of life span) and presented a greater predictive efficiency in females than in males. Taken together, our findings not only shed light on the genetic contributions to longevity but also elucidate correlations between diseases and longevity. This genetic association study of longevity on 15,651 Chinese individuals (3,448 nonagenarians and 2,509 centenarians) identified two novel human longevity loci. Two novel longevity loci, BMPER (rs17169634; p = 7.91 × 10−15) and TMEM43/XPC (rs1043943; p = 3.59 × 10−8) reached genome‐wide significance. Interestingly, gender differential associations revealed two linkage disequilibrium blocks on TOMM40/APOE region. In addition, our predictive models showed good performance (AUC = 0.86 for longevity classification and explained 19.8% variances of life span), and higher efficiencies in females than males. These findings provide potential strategies for improving healthy aging.