Meta‐analysis of genetic variants associated with human exceptional longevity

Abstract

Despite evidence from family studies that there is a strong genetic influence upon exceptional longevity, relatively few genetic variants have been associated with this trait. One reason could be that many genes individually have such weak effects that they cannot meet standard thresholds of genome wide significance, but as a group in specific combinations of genetic variations, they can have a strong influence. Previously we reported that such genetic signatures of 281 genetic markers associated with about 130 genes can do a relatively good job of differentiating centenarians from non‐centenarians particularly if the centenarians are 106 years and older. This would support our hypothesis that the genetic influence upon exceptional longevity increases with older and older (and rarer) ages. We investigated this list of markers using similar genetic data from 5 studies of centenarians from the USA, Europe and Japan. The results from the meta‐analysis show that many of these variants are associated with survival to these extreme ages in other studies. Since many centenarians compress morbidity and disability towards the end of their lives, these results could point to biological pathways and therefore new therapeutics to increase years of healthy lives in the general population.

Figure 1

Venn diagram showing the number of significant associations from the meta-analysis of additive, dominant and recessive models when a 6% false discovery rate (FDR) was used. Genotypes were called using the top-strand rule and dominant and recessive models were coded for the top-strand allele A as explained in methods.

Figure 2. Genetic effects versus allele frequency

Black circles= additive effects; Red asterisks: dominant effects; Green crosses= recessive effects.

Figure 3. Genes with SNPs that reach statistical significance with meta-analysis and were implicated in Alzheimer's and coronary artery disease

The two networks display 38 genes linked to Alzheimer's disease (top) and 24 genes linked to coronary artery disease (bottom) that included SNPs in the list of 281 in [1]. Genes circled in blue include SNPs that reached statistical significance in the meta-analysis.