Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne 1010, Switzerland.
Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
Nat Commun. 2017 Jul 27;8:15842. doi: 10.1038/ncomms15842.
The enormous variation in human lifespan is in part due to a myriad of sequence variants, only a few of which have been revealed to date. Since many life-shortening events are related to diseases, we developed a Mendelian randomization-based method combining 58 disease-related GWA studies to derive longevity priors for all HapMap SNPs. A Bayesian association scan, informed by these priors, for parental age of death in the UK Biobank study (n=116,279) revealed 16 independent SNPs with significant Bayes factor at a 5% false discovery rate (FDR). Eleven of them replicate (5% FDR) in five independent longevity studies combined; all but three are depleted of the life-shortening alleles in older Biobank participants. Further analysis revealed that brain expression levels of nearby genes (RBM6, SULT1A1 and CHRNA5) might be causally implicated in longevity. Gene expression and caloric restriction experiments in model organisms confirm the conserved role for RBM6 and SULT1A1 in modulating lifespan.
人类寿命的巨大差异部分归因于无数的序列变异，而迄今为止仅发现了其中的少数几种。由于许多缩短寿命的事件与疾病有关，因此我们开发了一种基于孟德尔随机化的方法，结合了 58 项与疾病相关的 GWAS 研究，为所有 HapMap SNPs 得出了长寿先验概率。通过这些先验概率，对英国生物库研究（n=116279）中父母死亡年龄进行贝叶斯关联扫描，在 5%的假发现率（FDR）下发现了 16 个具有显著贝叶斯因子的独立 SNP。其中 11 个在五个独立的长寿研究中得到了复制（5% FDR）；除了三个之外，所有这些 SNP 在年龄较大的生物库参与者中都没有缩短寿命的等位基因。进一步的分析表明，附近基因（RBM6、SULT1A1 和 CHRNA5）的脑表达水平可能与长寿有关。在模式生物中的基因表达和热量限制实验证实了 RBM6 和 SULT1A1 在调节寿命方面的保守作用。
