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

Abstract

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 <i>CDKN2B-AS1</i>, <i>ATXN2/BRAP</i>, <i>FURIN/FES</i>, <i>ZW10</i>, <i>PSORS1C3</i>, and 13q21.31, and identify and replicate novel findings near <i>ABO</i>, <i>ZC3HC1</i>, and <i>IGF2R</i>. We also validate previous findings near 5q33.3/<i>EBF1</i> and <i>FOXO3</i>, 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. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles. This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).