Genetic predisposition is believed to contribute substantially to the age at which we die. Genome-wide association studies (GWAS) have implicated more than 20 genetic loci to phenotypes related to human lifespan. However, little is known about how lifespan is impacted by gene loss-of-function. Through whole-exome sequencing of 238,239 UK Biobank participants, we assessed the relevance of protein-truncating variant (PTV) gene burden on individual and parental survival. We identified exome-wide (P<2.5e-6) significant associations between BRCA2, BRCA1, TET2, PPM1D, LDLR, EML2 and DEDD2 PTV-burden with human lifespan. Gene and gene-set PTV-burden phenome-wide association studies (PheWAS) further highlighted the roles of these genes in cancer and cardiovascular disease as relevant for overall survival. The overlap between PTV-burden and prior GWAS results was modest, underscoring the value of sequencing in well-powered cohorts to complement GWAS for identifying loci associated with complex traits and disease. ### Competing Interest Statement Jimmy Z. Liu, Chia-Yen Chen, Ellen A. Tsai, Christopher D. Whelan, David Sexton, Sally John and Heiko Runz are employees of Biogen
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