The February Journal Club will focus on the recent paper “Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances”. Hosted by Dr. Oliver Medvedik, we will be joined by study authors, Dr. Peter Joshi and Paul Timmers both from the University of Edinburgh, UK who will guide us through this fascinating genomics study of human longevity.
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 fetal 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.
Here, we blend three approaches to studying lifespan and perform the largest genome-wide association study (GWAS) on human lifespan to date. First, we leverage data from UK Biobank and 26 independent European-heritage population cohorts (Joshi et al., 2017) to carry out a GWAS of parental survival, quantified using Cox models. We then supplement this with data from 58 GWAS on mortality risk factors to conduct a Bayesian prior-informed GWAS (iGWAS). Finally, we use publicly available case-control longevity GWAS statistics to compare the genetics of lifespan and longevity and provide collective replication of our lifespan GWAS results.
We also examine the diseases associated with lifespan-altering variants and the effect of known disease variants on lifespan, to provide insight into the interplay between lifespan and disease. Finally, we use our GWAS results to implicate specific genes, biological pathways, and cell types, and use our findings to create and test whole-genome polygenic scores for survival.
The research paper can be found here.