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Meta-Analysis Links Two Loci to Shorter Lifespan in Humans

NEW YORK (GenomeWeb) – A University of Edinburgh-led team has linked two genetic variants, one located near the APOE gene and the other near the CHRNA3/5 gene, to a shortened lifespan.

As they reported today in Nature Communications, the Edinburgh researchers and their colleagues sifted through data contained within the UK Biobank to link the loci near the Alzheimer's disease-linked apolipoprotein E gene and the lung cancer-associated nicotinic acetylcholine receptor subunit alpha 5 gene to shorter lifespans. Age and sex further influenced the effects of these loci on lifespan, the researchers noted.

They estimated that the sliver of Europeans who are homozygous carriers of risk alleles at both loci would live lives some 3.3 years to 3.7 years shorter.

"Although the effect of these genetic variants on lifespan is surprisingly large, it is important to remember that this is only part of the story," first author Peter Joshi from the University of Edinburgh said in a statement. "Lifestyle has the greatest impact on how long we live and that is under our control."

Joshi and his colleagues turned to data amassed by the UK Biobank, and by linking parental lifespans to participants' genotypes, they zeroed in on 35 SNPs that were associated with lifespan in a meta-analysis. Only two of those — APOE and CHRNA3/5 — then reached genome-wide significance.

The researchers replicated this study in two sub-cohorts from the UK Biobank that weren't included in the initial analysis and a cohort from the Estonian Biobank. A meta-analysis of the replication cohorts and one of the combined discovery and replication cohorts further linked the loci near APOE and CHRNA3/5 to lifespan, with a similar effect size as the discovery set.

The APOE association with lifespan, they noted, was stronger among women, while the CHRNA3/5 association with lifespan was stronger among men.

They calculated that each APOE risk allele led to a 0.79 year and 1.24 years reduction in lifespan in men and women, respectively, while the CHRNA3/5 risk allele led to a 0.86 year and 0.6 year reduction in lifespan in men and women, respectively.

Variants in the APOE gene have previously been linked to Alzheimer's disease, as well as age-related cognitive decline and coronary disease risk. Here, Joshi and his colleagues suggested that the link they observed between the gene and lifespan could be due to its combined effects of cognitive decline and heart problems on mortality. They noted, too, that there have been reports that APOE strongly affects Alzheimer's risk in women.

The CHRNA5-CHRNA3-CHRNB4 locus, meanwhile, encodes a number of nicotinic acetyl choline receptor subunits, and SNPs in this region have be linked to nicotine dependence, lung cancer, and chronic obstructive pulmonary disease, and with airway obstruction specifically in people who have never smoked. It's not clear whether the effects at this locus are mediated by smoking behavior or are independent of smoking, the researchers said.

Age, Joshi and his colleagues found, also influences the effect of these variants. By comparing allele hazard ratios at age of deaths falling between 40 years old and 75 years old and over 75 years old, they found that that the effect of the APOE allele was larger at older ages. For instance, it was 1.09 in younger women, as compared to 1.2 in older women.

A less pronounced age effect was noted with CHRNA3/5 among men: the hazard ration for CHRNA3/5 was 1.1 in younger men and 1.03 in older men.

Still, the researchers noted that that the effect sizes of these loci are fairly large. They estimated that homozygous carriers of both risk alleles would have lives 3.3 years to 3.7 years shorter than carriers of protective alleles.

The effects of these loci on lifespan have largely been hidden from natural selection, Joshi and his colleagues added, as the effect of CHRNA3/5 is likely mediated by modern nicotine dependence and as APOE has its effect after child-bearing years.