Levine Morgan E, Crimmins Eileen M
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles.
Davis School of Gerontology, University of Southern California, Los Angeles.
J Gerontol A Biol Sci Med Sci. 2016 Jun;71(6):703-12. doi: 10.1093/gerona/glv141. Epub 2015 Sep 9.
Human longevity and diseases are likely influenced by multiple interacting genes within a few biologically conserved pathways. Using long-lived smokers as a phenotype (n = 90)-a group whose survival may signify innate resilience-we conducted a genome-wide association study comparing them to smokers at ages 52-69 (n = 730). These results were used to conduct a functional interaction network and pathway analysis, to identify single nucleotide polymorphisms that collectively related to smokers' longevity. We identified a set of 215 single nucleotide polymorphisms (all of which had p <5×10(-3) in the genome-wide association study) that were located within genes making-up a functional interaction network. These single nucleotide polymorphisms were then used to create a weighted polygenic risk score that, using an independent validation sample of nonsmokers (N = 6,447), was found to be significantly associated with a 22% increase in the likelihood of being aged 90-99 (n = 253) and an over threefold increase in the likelihood of being a centenarian (n = 4), compared with being at ages 52-79 (n = 4,900). Additionally, the polygenic risk score was also associated with an 11% reduction in cancer prevalence over up to 18 years (odds ratio: 0.89, p = .011). Overall, using a unique phenotype and incorporating prior knowledge of biological networks, this study identified a set of single nucleotide polymorphisms that together appear to be important for human aging, stress resistance, cancer, and longevity.
人类的寿命和疾病可能受到少数生物保守通路中多个相互作用基因的影响。我们以长寿吸烟者作为一种表型（n = 90）——这一群体的生存可能意味着其具有先天的恢复力——开展了一项全基因组关联研究，将他们与52 - 69岁的吸烟者（n = 730）进行比较。这些结果被用于进行功能相互作用网络和通路分析，以识别与吸烟者长寿相关的单核苷酸多态性。我们鉴定出一组215个单核苷酸多态性（在全基因组关联研究中所有这些多态性的p < 5×10(-3)），它们位于构成一个功能相互作用网络的基因内。然后利用这些单核苷酸多态性创建了一个加权多基因风险评分，在一个非吸烟者的独立验证样本（N = 6447）中发现，与52 - 79岁的人群（n = 4900）相比，该评分与90 - 99岁的可能性显著增加22%（n = 253）以及成为百岁老人的可能性增加三倍多（n = 4）显著相关。此外，多基因风险评分还与长达18年的癌症患病率降低11%相关（优势比：0.89，p = 0.011）。总体而言，本研究利用独特的表型并纳入生物网络的先验知识，鉴定出一组单核苷酸多态性，它们共同似乎对人类衰老、抗逆性、癌症和长寿很重要。
