A genome-wide study replicates linkage of 3p22-24 to extreme longevity in humans and identifies possible additional loci

Abstract

Background: Although 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 findings: We 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). 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/significance: Corroboration 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.

Figure 1. FLAG study linkage results for all autosomes.

A) nominal singlepoint p-values; B) nominal multipoint p-values.

Figure 2. Comparison of singlepoint linkage results for chromosome 3 under varying definitions of affected status (nominal p-values).

Figure 3. Comparison of chromosome 3 linkage results reported here to that reported by Boyden and Kunkel (nominal p-values).