Abstract
BackgroundAlthough there is abundant evidence that human longevity is heritable, efforts to map loci responsible for variation in human lifespan have had limited success.Methodology/Principal FindingsWe identified individuals from a large multigenerational population database (the Utah Population Database) who exhibited high levels of both familial longevity and individual longevity. This selection identified 325 related “affected individuals”, defined as those in the top quartile for both excess longevity (EL = observed lifespan – expected lifespan) and familial excess longevity (FEL = weighted average EL across all relatives). A whole-genome scan for genetic linkage was performed on this sample using a panel of 1100 microsatellite markers. A strongly suggestive peak (Z = 4.2, Monte Carlo-adjusted p-value 0.09) was observed in the vicinity of D3S3547 on chromosome 3p24.1, at a point nearly identical to that reported recently by an independent team of researchers from Harvard Medical School (HMS) [1]. Meta-analysis of linkage scores on 3p from the two studies produced a minimum nominal p-value of 1.005×10−9 at 55 cM. Other potentially noteworthy peaks in our data occur on 18q23-24, 8q23, and 17q21. Meta-analysis results from combined UPDB and HMS data yielded additional support, but not formal replication, for linkage on 8q, 9q, and 17q.Conclusions/SignificanceCorroboration of the linkage of exceptional longevity to 3p22-24 greatly strengthens the case that genes in this region affect variation in longevity and suggest, therefore, an important role in the regulation of human lifespan. Future efforts should include intensive study of the 3p22-24 region.
Highlights
It has long been thought that related individuals share a familial predisposition to longevity, and for more than a century numerous studies have investigated the degree to which human longevity might be an inherited characteristic [2,3,4,5,6,7,8,9,10,11,12]
Subjects In two previous studies, we examined the influence of family history on longevity in the Utah Population Database (UPDB): we defined excess longevity (EL) as the difference between observed and expected lifespan for an individual; and we defined familial excess longevity (FEL) as a kinshipweighted average of EL across all the family members of a subject [11,12]
One immediate result of the FLAG study scan is an independent replication of Boyden and Kunkel’s finding of a genetic linkage between excess longevity and a locus in the 3p2224 region in the Harvard Medical School (HMS) data
Summary
It has long been thought that related individuals share a familial predisposition to longevity, and for more than a century numerous studies have investigated the degree to which human longevity might be an inherited characteristic [2,3,4,5,6,7,8,9,10,11,12] Most studies of this type have reported small (,10%) to moderate (,30%) heritability of human longevity, amid differences in definitions of longevity, methods of measuring it, ascertaining individuals who demonstrate it, and in various behavioral and environmental settings. There is abundant evidence that human longevity is heritable, efforts to map loci responsible for variation in human lifespan have had limited success
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