Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62,488 common and rare coding variants in 1,248 German long-lived individuals, including 599 centenarians and 6,941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery P-value (1x10E-04). Furthermore, we validated the previously reported longevity locus cyclin dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified two new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, i.e. the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP).
GrantsMunich Center of Health Sciences (MC Health), Ludwig-Maximilians Universitat, LMU innovativ German Federal Ministry of Education and Research (BMBF) BMBF Ministere de l'Enseignement superieur et de la Recherche French Institut National de la Sante et de la Recherche Medicale Institut National de la Recherche Agronomique Universite Paris 13 Commissariat a l'Energie Atomique-Centre National de Recherche en Genomique Humaine National Program for Research Infrastructure Danish Agency for Science Technology and Innovation Velux Foundation U.S. National Institute of Health NIH Helmholtz Zentrum Munchen - German Research Center for Environmental Health - BMBF State of Bavaria Cluster of Excellence "Inflammation at Interfaces"