Abstract
We have completed a genome-wide linkage scan for healthy aging using data collected from a family study, followed by fine-mapping by association in a separate population, the first such attempt reported. The family cohort consisted of parents of age 90 or above and their children ranging in age from 50 to 80. As a quantitative measure of healthy aging, we used a frailty index, called FI34, based on 34 health and function variables. The linkage scan found a single significant linkage peak on chromosome 12. Using an independent cohort of unrelated nonagenarians, we carried out a fine-scale association mapping of the region suggestive of linkage and identified three sites associated with healthy aging. These healthy-aging sites (HASs) are located in intergenic regions at 12q13-14. HAS-1 has been previously associated with multiple diseases, and an enhancer was recently mapped and experimentally validated within the site. HAS-2 is a previously uncharacterized site possessing genomic features suggestive of enhancer activity. HAS-3 contains features associated with Polycomb repression. The HASs also contain variants associated with exceptional longevity, based on a separate analysis. Our results provide insight into functional genomic networks involving non-coding regulatory elements that are involved in healthy aging and longevity.
Highlights
Aging can be defined as the occurrence of changes over time that adversely affect the vitality and functions, increasing the mortality rate [1]
Because the healthy aging phenotype data were unavailable for Healthy Aging Family Study (HAFS) parents, we inferred healthy aging status of each parent from the parent-offspring linear regression, where the slope of the regression line is mathematically equivalent to the narrow-sense heritability of FI34
According to recent database statistics compiled by LongevityMap, of the total 755 loci studied for their associations with human aging and longevity, 257 were entered as significant [20]
Summary
Aging can be defined as the occurrence of changes over time that adversely affect the vitality and functions, increasing the mortality rate [1]. The onset of aging varies from individual to individual, and the agingrelated changes occur at different rates in different individuals at many levels of biological organization. This complex phenomenon has both genetic and non-genetic underpinnings [2, 3]. One quantitative indicator of the genetic basis of a complex trait is heritability, which is a measure of the extent of genetic control of the trait. The heritability of human longevity ranges from 0.15 to 0.35 [6, 7], which implies that 65–85% of the trait can be controlled by non-genetic factors. Studies indicate that survival to older ages is under stronger genetic influence. Long-lived people are likely to carry more beneficial genetic variants, fewer harmful variants or both
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