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.
Highlights
Lifespan is a trait of enormous personal interest
The use of phenotyped relatives of subjects who have been genotyped to conduct association analyses between phenotype and probabilistically inferred genotype, generalizes the approach of Wacholder et al.[9] from Mendelian traits to quantitative traits and provides a step change in power, applicable to all late onset conditions, where direct genotyping may be problematic. We use this approach to show that common variants near the apolipoprotein E and nicotinic acetylcholine receptor subunit alpha 5 genes are associated with lifespan in a sex- and agedependent manner
In the discovery phase genome-wide association (GWAS), using rank-normalized Martingale residuals of survivorship for 116,425 UKB subjects of unambiguous British genetic ancestry, we discovered 35 single nucleotide polymorphisms (SNPs) (Supplementary Table 1) with a P value o10 À 6 for association in meta-analysis of paternal and maternal lifespans
Summary
Lifespan is a trait of enormous personal interest. Research into the biological basis of human lifespan, is hampered by the long time to death. Efforts to discover additional age-related genetic loci are impeded by difficulties in recruiting very large prospective cohorts with lifespan and genomic data that are required to give sufficient power to detect the expected small effects associated with this complex trait. The use of phenotyped (but not genotyped) relatives of subjects who have been genotyped to conduct association analyses between phenotype and probabilistically inferred genotype, generalizes the approach of Wacholder et al.[9] from Mendelian traits to quantitative traits and provides a step change in power, applicable to all late onset conditions, where direct genotyping may be problematic We use this approach to show that common variants near the apolipoprotein E and nicotinic acetylcholine receptor subunit alpha 5 genes are associated with lifespan in a sex- and agedependent manner. The major genetic determinants of lifespan are both very pleiotropic disease susceptibility genes
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