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

Luke C. Pilling, Janice L. Atkins, Kirsty Bowman, Samuel E. Jones, Jessica Tyrrell, Robin N. Beaumont, Katherine S. Ruth, Marcus A. Tuke, Hanieh Yaghootkar, Andrew R. Wood, Rachel M. Freathy, Anna Murray, Michael N. Weedon, Luting Xue, Kathryn Lunetta, Joanne M. Murabito, Lorna W. Harries, Jean Marie Robine, Carol Brayne, George A. KuchelLuigi Ferrucci, Timothy M. Frayling, David Melzer

Research output: Contribution to journalArticle

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=5.7x10-3). 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.

Original languageEnglish (US)
Pages (from-to)547-560
Number of pages14
JournalAging
Volume8
Issue number3
Publication statusPublished - Mar 1 2016

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Keywords

  • aging
  • genetic
  • GWAS
  • human
  • longevity

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Pilling, L. C., Atkins, J. L., Bowman, K., Jones, S. E., Tyrrell, J., Beaumont, R. N., ... Melzer, D. (2016). Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants. Aging, 8(3), 547-560.