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.

Figure 1. Genome-wide association with parental lifespan.

Manhattan plots are presented for the discovery analysis in genetically British individuals (a) for fathers, (b) for mothers, (c) for meta-analysis of parents. In each case the trait is the Martingale residuals of the Cox proportional hazards model of parental lifespan. rs429358 and rs10519203 explain, respectively, 0.026/0.068% and 0.042/0.012% of the variance of the Martingale residuals in fathers/mothers.

Figure 2. Locus zoom plots for the two robust associations with parental lifespan.

(a) CHRNA3/5 region and paternal lifespan, (b) APOE region and maternal lifespan.