TY - JOUR T1 - Human Longevity is Influenced by Many Genetic Variants: Evidence from 75,000 UK Biobank Participants JF - bioRxiv DO - 10.1101/038430 SP - 038430 AU - Luke C. Pilling AU - Janice L. Atkins AU - Kirsty Bowman AU - Samuel E. Jones AU - Jessica Tyrrell AU - Robin N. Beaumont AU - Katherine S. Ruth AU - Marcus A. Tuke AU - Hanieh Yaghootkar AU - Andrew R. Wood AU - Rachel M. Freathy AU - Anna Murray AU - Michael N. Weedon AU - Luting Xue AU - Kathryn Lunetta AU - Joanne M. Murabito AU - Lorna W. Harries AU - Jean-Marie Robine AU - Carol Brayne AU - George A. Kuchel AU - Luigi Ferrucci AU - Timothy M. Frayling AU - David Melzer Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/02/01/038430.abstract N2 - Variation in human lifespan is 20 to 30% heritable but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father’s and/or mother’s data). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested.Genotyped variants (n=845,997) explained 10.2% (SD=1.3%) of combined parental longevity. In GWAS, a locus in the nicotine receptor CHRNA3 – previously associated with increased smoking and lung cancer - was associated with paternal age at death, with each protective allele (rs1051730[G]) being associated with 0.03 years later age at father’s death (p=3x10-8). Offspring of longer lived parents had more protective alleles (lower genetic risk scores) for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer’s disease. In candidate gene analyses, variants in the TOMM40/APOE locus were associated with longevity (including rs429358, p=3x10-5), but FOXO variants were not associated.These results support a multiple protective factors model for achieving longer lifespans in humans, with a prominent role for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable. ER -