Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances

We use a 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 ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-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 show a mean lifespan difference of around five years of life across the deciles.

Timmers, Paul R H J; Läll, Kristi; Fischer, Krista; Ning, Zheng; Feng, Xiao; Bretherick, Andrew; Clark, David W; Shen, Xia; Esko, Tōnu; Kutalik, Zoltán; Wilson, James F; Joshi, Peter K. (2018). Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances, [dataset]. Usher Institute of Population Health Sciences and Informatics.