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Torres, G.G.* ; Nygaard, M.* ; Caliebe, A.* ; Blanché, H.* ; Chantalat, S.* ; Galan, P.* ; Lieb, W.* ; Christiansen, L.* ; Deleuze, J.F.* ; Christensen, K.* ; Strauch, K. ; Müller-Nurasyid, M. ; Peters, A. ; Nöthen, M.M.* ; Hoffmann, P.* ; Flachsbart, F.* ; Schreiber, S.* ; Ellinghaus, D.* ; Franke, A.* ; Dose, J.* ; Nebel, A.*

Exome-wide association study identifies FN3KRP and PGP as new candidate longevity genes.

J. Gerontol. A Biol. Sci. Med. Sci. 76, 786–795 (2021)
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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).
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Publication type Article: Journal article
Document type Scientific Article
Keywords Association Study ; Healthy Aging ; Humanexome Beadchip ; Long-lived Individuals ; Rare Variants; Confirms Apoe; Rare; Metaanalysis; Variants; Survival; Metabolism; Glycation; Pathways; Locus; Tests
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 1079-5006
e-ISSN 1758-535X
Journal Journals of Gerontology Series A: Biological Sciences and Medical Sciences
Quellenangaben Volume: 76, Issue: 5, Pages: 786–795 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504100-001
Grants Munich 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"
DOI 10.1093/gerona/glab023
WOS ID WOS:000656221600006
Scopus ID 85106069969
PubMed ID 33491046
Erfassungsdatum 2021-04-13
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