Abstract
Heritability of human lifespan is 23-33% as evident from twin studies. Genome-wide association studies explored this question by linking particular alleles to lifespan traits. However, genetic variants identified so far can explain only a small fraction of lifespan heritability in humans. Here, we report that the burden of rarest protein-truncating variants (PTVs) in two large cohorts is negatively associated with human healthspan and lifespan, accounting for 0.4 and 1.3 years of their variability, respectively. In addition, longer-living individuals possess both fewer rarest PTVs and less damaging PTVs. We further estimated that somatic accumulation of PTVs accounts for only a small fraction of mortality and morbidity acceleration and hence is unlikely to be causal in aging. We conclude that rare damaging mutations, both inherited and accumulated throughout life, contribute to the aging process, and that burden of ultra-rare variants in combination with common alleles better explain apparent heritability of human lifespan.
Highlights
Genome-wide association studies (GWAS) of human lifespan, including studies examining extreme longevity, parental survival, and healthspan, produced a number of gene variants associated with human longevity
We tested the effects of damaging gene variants on healthspan, that is the disease-free period
We examined the association of protein-truncating variants (PTVs) load in the defined minor allele frequency (MAF) bins against the selected longevity traits using Cox proportional hazards (PH) models
Summary
Genome-wide association studies (GWAS) of human lifespan, including studies examining extreme longevity, parental survival, and healthspan, produced a number of gene variants associated with human longevity. Release of massive genotype and phenotype data by UK Biobank (UKB)[2] inspired investigation of the relationship between genetics and longevity proxies, such as parental lifespan[3] and healthspan within general population[4]. They confirmed most of the variants from centenarian studies and identified additional variants. The combined contribution of these variants could explain only a small part of lifespan heritability, at least as asserted from twin studies[5]. The large datasets such as gnomAD and UKB allow assessing the effects of variants with minor allele frequency (MAF) lower than 0.1%
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