Variants near CHRNA3/5 and APOE have age- and sex-related effects on human lifespan

• Published in: Nature communications Vol. 7; no. 1; pp. 11174 - 7
• Main Authors: Joshi, Peter K., Fischer, Krista, Schraut, Katharina E., Campbell, Harry, Esko, Tõnu, Wilson, James F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.03.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/726/649; 631/443/7; Adult; Age Factors; Aged; Aged, 80 and over; Apolipoproteins E - genetics; Apolipoproteins E - physiology; Cohort Studies; Female; Genome-Wide Association Study; Genotype; Humanities and Social Sciences; Humans; Life span; Longevity - genetics; Male; Middle Aged; multidisciplinary; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Proportional Hazards Models; Receptors, Nicotinic - genetics; Receptors, Nicotinic - physiology; Science; Science (multidisciplinary); Sex Factors; United Kingdom
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11174

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. Understanding the genetic influences on human aging requires a large number of subjects for a study of sufficient power. Here, Jim Wilson and colleagues use information on parental ages at death to show that common variants near the genes for apolipoprotein E and nicotinic acetylcholine receptor subunit alpha 5 are associated with longer lifespan.