title: Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants.
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.
authors.affiliation: Epidemiology and Public Health Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Luke C
authors.initials: LC
authors.lastname: Pilling
authors.affiliation: Epidemiology and Public Health Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Atkins
authors.affiliation: Epidemiology and Public Health Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Bowman
authors.affiliation: Genetics of Complex Traits Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Jones
authors.affiliation: Genetics of Complex Traits Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tyrrell
authors.affiliation: Genetics of Complex Traits Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Robin N
authors.initials: RN
authors.lastname: Beaumont
authors.affiliation: Genetics of Complex Traits Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Ruth
authors.affiliation: Genetics of Complex Traits Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Tuke
authors.affiliation: Genetics of Complex Traits Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Hanieh
authors.initials: H
authors.lastname: Yaghootkar
authors.affiliation: Genetics of Complex Traits Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Wood
authors.affiliation: Genetics of Complex Traits Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Freathy
authors.affiliation: Genetics of Complex Traits Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Murray
authors.affiliation: Genetics of Complex Traits Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.affiliation: School of Public Health, Department of Biostatistics, Boston University, Boston, MA 02215, USA.
authors.forename: Luting
authors.initials: L
authors.lastname: Xue
authors.affiliation: School of Public Health, Department of Biostatistics, Boston University, Boston, MA 02215, USA.|The Framingham Heart Study, Framingham, MA 01702, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Lunetta
authors.affiliation: The Framingham Heart Study, Framingham, MA 01702, USA.|Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Murabito
authors.affiliation: Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM U1198), 34394 Montpellier, France.|Ecole Pratique des Hautes études (EPHE), 75014 Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Robine
authors.affiliation: Cambridge Institute of Public Health, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SR, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.affiliation: Center on Aging, University of Connecticut, Farmington, CT 06030, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Kuchel
authors.affiliation: National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: Genetics of Complex Traits Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.affiliation: Epidemiology and Public Health Group, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Exeter, EX2 5DW, UK.|Center on Aging, University of Connecticut, Farmington, CT 06030, USA.
authors.forename: David
authors.initials: D
authors.lastname: Melzer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D030541:Databases, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012907:Smoking / Q000235:genetics; D006113:United Kingdom
keywords: GWAS; aging; genetic; human; longevity