Aging
Navigate
Research Paper|Volume 8, Issue 3|pp 547—560

Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants

Luke C. Pilling1, Janice L. Atkins1, Kirsty Bowman1, Samuel E. Jones2, Jessica Tyrrell2, Robin N. Beaumont2, Katherine S. Ruth2, Marcus A. Tuke2, Hanieh Yaghootkar2, Andrew R. Wood2, Rachel M. Freathy2, Anna Murray2, Michael N. Weedon2, Luting Xue3, Kathryn Lunetta3,4, Joanne M. Murabito4,5, Lorna W. Harries6, Jean-Marie Robine7,8, Carol Brayne9, George A. Kuchel10, Luigi Ferrucci11, Timothy M. Frayling2, David Melzer1,10
  • 1Epidemiology and Public Health Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK
  • 2Genetics of Complex Traits Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK
  • 3School of Public Health, Department of Biostatistics, Boston University, Boston, MA 02215, USA
  • 4The Framingham Heart Study, Framingham, MA 01702, USA
  • 5Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
  • 6Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK
  • 7Institut National de la Santé et de la Recherche Médicale (INSERM U1198), 34394 Montpellier, France
  • 8Ecole Pratique des Hautes études (EPHE), 75014 Paris, France
  • 9Cambridge Institute of Public Health, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SR, UK
  • 10Center on Aging, University of Connecticut, Farmington, CT 06030, USA
  • 11National Institute on Aging, Baltimore, MD 21224, USA
Received: February 5, 2016Accepted: March 10, 2016Published: March 23, 2016

Copyright: © 2016 Pilling et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Variation in human lifespan is 20 to 30% heritable in twins 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, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus (CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles 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 analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7×10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.