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

Abstract

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.

Lifespan-Associated Gene Expression Signatures of Recombinant BXD Mice Implicates Coro7 and Set in Longevity

“…Furthermore, sex differences for longevity are recently more reported (Mitchell et al, 2016). For instance, a recent study found sex-specific single nucleotide polymorphism for human longevity genes, including the most common identified longevity loci TOMM40 and APOE (Liu et al, 2021). Thus, future studies should attempt to parse the data in a sex-specific manner to more accurately determine these gender-specific signatures.…”

Leisure Activities, APOE ε4, and Cognitive Decline: A Longitudinal Cohort Study

“…These candidate SNPs were selected based on previously published associations with longevity, chronic diseases, and health indicators. Further details on the genotyping platform, sample filtering, and quality control can be found in our published work (Zeng et al, 2016 ; Liu et al, 2021 ). Consistent with prior studies, we determined APOE genotypes using the two SNPs: rs429358 and rs7412 (Zhu et al, 2020 ).…”

TOMM40 RNA Transcription in Alzheimer’s Disease Brain and Its Implication in Mitochondrial Dysfunction

“…Genetic associated signals of TOMM40 in AD have traditionally been dismissed as surrogate signals of APOE [46,47]; however, this viewpoint has gradually shifted to consider TOMM40 as an independent contributor to AD risk and healthy aging. For example, genetic variants in TOMM40 have been consistently linked to longevity and healthy aging [48][49][50][51]. The SNP rs2075650 located in intron 2 of TOMM40 has been considered a proxy of the SNP rs429358 that defines the ε4 allele of APOE [29].…”