A Novel Longevity-Associated Genetic Locus in Humans

Finding genetic correlations with longevity in humans is challenging. All results found to date produce only small statistical effects, and very few indeed can be replicated between different study populations. This suggests that genetic contributions to longevity are diffuse and highly variable. Any single difference contributes very little, and that contribution is contingent on many other differences, such that any given regional population will have a very different map of genetic variations to longevity differences.

Here is a rare example of a more robust association between a genetic locus and longevity, and you'll note that as for other results the statistical effect on mortality is small. The paper is open access, but the full text is PDF only.

The genetic contribution to the variation in human lifespan is approximately 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (older than 85 years) and 16121 younger controls (younger than 65 years) followed by replication in an additional set of 13060 long-lived individuals and 61156 controls. In addition, we performed a subset analysis in cases older than 90 years.

We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3. We also confirmed association of rs4420638 on chromosome 19q13.32, representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival with a hazard ratio of 0.95. This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure.

We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Link: http://dx.doi.org/10.1093/hmg/ddu139

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