title: Variants near CHRNA3/5 and APOE have age- and sex-related effects on human lifespan.
abstract: Lifespan is a trait of enormous personal interest. Research into the biological basis of human lifespan, however, is hampered by the long time to death. Using a novel approach of regressing (272,081) parental lifespans beyond age 40 years on participant genotype in a new large data set (UK Biobank), we here show that common variants near the apolipoprotein E and nicotinic acetylcholine receptor subunit alpha 5 genes are associated with lifespan. The effects are strongly sex and age dependent, with APOE ɛ4 differentially influencing maternal lifespan (P=4.2 × 10(-15), effect -1.24 years of maternal life per imputed risk allele in parent; sex difference, P=0.011), and a locus near CHRNA3/5 differentially affecting paternal lifespan (P=4.8 × 10(-11), effect -0.86 years per allele; sex difference P=0.075). Rare homozygous carriers of the risk alleles at both loci are predicted to have 3.3-3.7 years shorter lives.
authors.affiliation: Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, Scotland.
authors.forename: Peter K
authors.identifier: http://orcid.org/0000-0002-6361-5059
authors.initials: PK
authors.lastname: Joshi
authors.affiliation: Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia.
authors.forename: Krista
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, Scotland.|Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh EH16 4TJ, Scotland.
authors.forename: Katharina E
authors.initials: KE
authors.lastname: Schraut
authors.affiliation: Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, Scotland.
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.affiliation: Estonian Genome Center, University of Tartu, Riia 23b, 51010 Tartu, Estonia.|Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, Massachusetts 02141, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, Massachusetts 02242, USA.|Department of Genetics, Harvard Medical School, 25 Shattuck St, Boston, Massachusetts 02115, USA.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, Scotland.|MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland.
authors.forename: James F
authors.identifier: http://orcid.org/0000-0001-5751-9178
authors.initials: JF
authors.lastname: Wilson
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001057:Apolipoproteins E / Q000235:genetics* / Q000502:physiology; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D016016:Proportional Hazards Models; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000502:physiology; D012737:Sex Factors; D006113:United Kingdom
chemical_list: D001057:Apolipoproteins E; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human