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Genomic underpinnings of lifespan allow prediction and reveal basis in modern risks

By Paul Timmers, Ninon Mounier, Kristi Läll, Krista Fischer, Zheng Ning, Xiao Feng, Andrew Bretherick, David W Clark, eQTLGen Consortium, Xia Shen, Tōnu Esko, Zoltán Kutalik, James F Wilson, Peter Joshi

Posted 06 Jul 2018
bioRxiv DOI: 10.1101/363036

We use a multi-stage genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near GADD45G, KCNK3, LDLR, POM121C, ZC3HC1, and ABO. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and tissue-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer, but not other cancers, explain the most variance, possibly reflecting modern susceptibilities, whilst cancer may act through many rare variants, or the environment. Resultant polygenic scores predict a mean lifespan difference of around five years of life across the deciles.

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