1. Bayesian association scan reveals loci associated with human lifespan and linked biomarkers.
- Author
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McDaid AF, Joshi PK, Porcu E, Komljenovic A, Li H, Sorrentino V, Litovchenko M, Bevers RPJ, Rüeger S, Reymond A, Bochud M, Deplancke B, Williams RW, Robinson-Rechavi M, Paccaud F, Rousson V, Auwerx J, Wilson JF, and Kutalik Z
- Subjects
- Aged, Aged, 80 and over, Arylsulfotransferase genetics, Bayes Theorem, Biomarkers analysis, Disease genetics, Female, Genome-Wide Association Study, Humans, Male, Nerve Tissue Proteins genetics, RNA-Binding Proteins genetics, Receptors, Nicotinic genetics, United Kingdom, White People genetics, Longevity genetics, Polymorphism, Single Nucleotide
- Abstract
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.
- Published
- 2017
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