IL20RB, interleukin 20 receptor beta IL-20, plays a role in skin inflammation and the development of hematopoi- etic cells (50) and is of interest because of the strong asso- ciations of inflammation with the aging process (51). IL-20 is a pleiotropic cytokine with potent inflammatory, angio- genic, and chemoattractive characteristics and is involved in inflammatory diseases, such as psoriasis, atherosclero- sis, and rheumatoid arthritis (50). The ACCN1 gene en- codes amiloride-sensitive sodium channels with two hydrophobic transmembrane regions and a large extracel- lular loop, which has many cysteine residues with con- served spacing (52,53). The member encoded by this gene may play a role in neurotransmission. ACCN1 was found to be associated with multiple sclerosis (54). Pregnancy-asso- ciated plasma protein A2 (PAPPA2) is a metalloproteinase regulating local insulin-like growth factor pathway action (55). Genetic deletion extends life span in the mouse by 30%–40% (56) and is characterized by delay in thymic in- volution (57) and low rates of tumor incidence (56). Al- though the associations reported here did not reach the a priori specified level of significance, the findings are im- portant to report so that they can be replicated in studies without whole-genome genotyping and compared with fu- ture studies, such as in centenarian studies and family stud- ies of longevity. Effect size estimates noted here support

for birth cohort, but the overlap between birth year of the comparison group and of the long-lived participants was limited. Further follow-up of these cohorts is needed to in- crease our ability to examine potential birth cohort effects. The study design of the cohorts examined in the second stage was different from the initial four-study CHARGE meta-analysis in that the comparison groups were derived from younger participants, living and deceased, who were not from the same cohort as the individuals achieving lon- gevity. Certainly, there are important environmental factors that would be necessary for the fulfillment of the genetic potential for longevity. Heterogeneity in environmental ex- posures and gene–environment interactions require further study. Finally, these results cannot be extended to popula- tions 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, addi- tional 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 nec- essarily 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

Acknowledgments

Funding

We are indebted to the participants and staff in the AGES-Reykjavik, the CHS, the FHS, and the RS for their important contributions. We acknowl- edge the NHLBI, which has made the Framingham SNP Health Association Resource project possible.