Figure 1. Quantile-quantile plot for the 2,287,520 single-nucleotide polymorphisms in the meta-analysis of survival to ageProtein-A2 (PAPPA2) is a gene that encodes a protein involved in insulin-like growth factor (IGF) signaling. The IGF pathway has been implicated in aging and age-related diseases, such as cancer and cardiovascular disease (55). The inconsistent direction of association for the other SNPs highlights the complex nature of longevity, suggesting that there may be many genes with small effects that contribute to this trait. 

The collaboration of the CHARGE Consortium allowed for a meta-analysis of genome-wide association studies (GWAS) for longevity in a sample of long-lived individuals and a comparison group from the same longitudinal community-based cohort studies. Although none of the SNP associations achieved genome-wide significance in the first discovery phase, a polymorphism associated with the MINPP1 gene was among the strongest associations observed in the sample, with effect sizes similar within all four cohorts. The finding related to the MINPP1 gene was strengthened after including two additional cohorts in a second discovery phase but did not reach genome-wide significance. 

Among the top 10 associations in the initial meta-analysis, additional SNP associations of potential interest in longevity include SNPs in or near LASS3, ACCN1, IL20RB, and PAPPA2. These SNPs are near genes that have not previously been reported to be associated with longevity in human populations but are interesting because these genes are conserved in basic biological pathways.

The strengths of this study include its community-based prospective design, long-term follow-up of cohorts, and use of controls drawn from within the same cohorts. The large number of long-lived individuals reported here is greater than other studies in literature, allowing for greater ability to identify SNPs with small effects. However, differences in causes of death between long-lived individuals and comparison groups are expected as death from cancer tends to occur earlier in life than death from heart disease or dementia.

In summary, this study suggests that longevity is a complex trait and that there may be many genes with small effects that contribute to this trait. The findings related to the MINPP1 gene and other SNPs near conserved genes in basic biological pathways are of potential interest in longevity research. Future GWAS aiming to identify variants for this phenotype will have to consider small effect sizes and target a sample size larger than the nearly 2,000 long-lived individuals in this study.healthspan in mice. Nature. 2003; 421(6920):182-187.

Protein A2 (PAPPA2) is a metalloproteinase that regulates the local insulin-like growth factor pathway action (55). Genetic deletion extends lifespan in mice by 30-40% (56) and is characterized by a delay in thymic involution (57) and low rates of tumor incidence (56). Although the associations reported here did not reach the a priori specified level of significance, the findings are important to report so that they can be replicated in studies without whole-genome genotyping and compared with future studies, such as in centenarian studies and family studies of longevity. Effect size estimates noted here support birth cohort, but the overlap between the birth year of the comparison group and that of the long-lived participants was limited. Further follow-up of these cohorts is needed to increase our ability to examine potential birth cohort effects. The study design of the cohorts examined in the second stage was different from that of the initial four-study CHARGE meta-analysis because the comparison groups were derived from younger participants, both living and deceased, who were not from the same cohort as those achieving longevity. Certainly, there are important environmental factors that would be necessary for the fulfillment of the genetic potential for longevity. Heterogeneity in environmental exposures and gene-environment interactions requires further study. Finally, these results cannot be extended to populations of other ancestry.

In conclusion, this meta-analysis of GWAS data for longevity from four large cohorts and two additional cohorts has implicated several genes involved in conserved basic mechanisms of cellular function. Analysis of more extreme survival phenotypes such as centenarians, additional follow-up to increase sample size in these cohorts for this phenotype, or evaluation of more specific phenotypes such as disease-free survival may support and refine these initial findings.

Conflict of Interest: The content is solely the responsibility of the authors and does not necessarily represent the views of the NIA, NHLBI, the National Institute of Neurological Disorders and Stroke, or NIH.

Supplementary material can be found at: http://biomed.gerontologyjournals.