This is the final version of the article. Available from the publisher via the DOI in this record.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.This work was generously funded by an award to DM,
TF, AM, LH and CB by the Medical Research Council
MR/M023095/1. This research has been conducted
using the UK Biobank Resource, under application
1417. The authors wish to thank the UK Biobank
participants and coordinators for this unique dataset.
S.E.J. is funded by the Medical Research Council
(grant: MR/M005070/1). J.T. is funded by a Diabetes
Research and Wellness Foundation Fellowship. R.B. is
funded by the Wellcome Trust and Royal Society grant:
104150/Z/14/Z. M.A.T., M.N.W. and A.M. are
supported by the Wellcome Trust Institutional Strategic
Support Award (WT097835MF). R.M.F. is a Sir Henry
Dale Fellow (Wellcome Trust and Royal Society grant:
104150/Z/14/Z). A.R.W. H.Y., and T.M.F. are
supported by the European Research Council grant:
323195:GLUCOSEGENES-FP7-IDEAS-ERC. The
funders had no influence on study design, data
collection and analysis, decision to publish, or
preparation of the manuscript.
The Framingham Heart Study is supported by Contract
No. N01-HC-25195 and HHSN268201500001I and its
contract with Affymetrix, Inc for genotyping services
(Contract No. N02-HL-6-4278). The phenotypegenotype
association analyses were supported by
National Institute of Aging R01AG29451.
This work has made use of the resources provided by
the University of Exeter Science Strategy and resulting
Systems Biology initiative. Primarily these include
high-performance computing facilities managed by
Konrad Paszkiewicz of the College of Environmental
and Life Sciences and Pete Leggett of the University of
Exeter Academics services unit
