Abstract
Genetic influences have an important role in the ageing process. The genetic factors that influence success in bodily ageing may also contribute to the successful ageing of cognitive abilities. A comparative genomics approach found longevity genes conserved between yeast Saccharomyces cerevisiae and nematode Caenorhabditis elegans. We hypothesised that these longevity genes influence variance in cognitive ability and age-related cognitive decline in humans. Here, we investigated six of these genes that have human orthologs and show expression in the brain. We tested AFG3L2 (MIM: 604581, AFG3 ATPase family gene 3-like 2 (yeast)), FRAP1 (MIM: 601231, a FK506 binding protein 12-rapamycin associated protein), MAT1A, MAT2A (MIM: 610550 and 601468, methionine adenosyltransferases I alpha and II alpha, respectively), SYNJ1 and SYNJ2 (MIM: 604297 and 609410, synaptojanin-1 and synaptojanin-2, respectively) in approximately 1000 healthy older Scots: the Lothian Birth Cohort 1936 (LBC1936). They were tested on general cognitive ability at age 11 years. At a mean age of 70 years, they re-sat the same general cognitive ability test and underwent an additional battery of diverse cognitive tests. In all, 70 tag and functional SNPs in the six longevity genes were genotyped and tested for association with cognition and cognitive ageing in LBC1936. Suggestive associations were detected between SNPs in SYNJ2, MAT1A, AFG3L2 and SYNJ1 and a general memory factor and general cognitive ability at age 11 and 70 years. Replication studies for cognitive ability associations were performed in 2506 samples from the Cognitive Ageing Genetics in England and Scotland consortium. A meta-analysis replicated the SYNJ2 association with cognitive abilities (lowest P=0.00077). SYNJ2 is a novel gene in which variation is potentially associated with cognitive abilities.
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Acknowledgements
We thank the cohort participants and team members who contributed to these studies. Genotyping of the CAGES cohorts and the analyses conducted here were supported by the UK's Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK's The Disconnected Mind project). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the BBSRC, The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Aberdeen Birth Cohort 1936 was supported by BBSRC, the Welcome Trust and the Alzheimer's Research trust. Phenotype collection in the Manchester and Newcastle Longitudinal Studies of Cognitive Aging cohorts was supported by Social Science Research Council, Medical Research Council, Economic and Social Research Council, Research Into Ageing, Wellcome Trust and Unilever plc. LML is supported by AXA Research Fund during some of this work. ML is a Royal Society of Edinburgh/Lloyds TSB Foundation for Scotland Personal Research Fellow. The work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged.
Author Contributions
Data analysis: Lopez. Study design: Lopez and Deary. Manuscript Preparation: Lopez, Deary, Harris, Luciano, Gow, Starr and Pendleton. Individual study design/management: Tenesa, Payton, Ke, Whalley, Fox, Ollier, Pickles, Porteous, Horan, Pendleton, Starr and Deary. Genetic preparation: Lopez, Liewald, Davies, Harris, Luciano and Tenesa. Phenotype preparation: Lopez, Luciano, Gow, Payton, Ke, Whalley, Fox, Ollier, Pickles, Horan, Pendleton, Starr and Deary. Manuscript review: Lopez, Harris, Luciano, Liewald, Davies, Gow, Tenesa, Payton, Ke, Whalley, Fox, Ollier, Pickles, Porteous, Horan, Pendleton, Starr and Deary.
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Lopez, L., Harris, S., Luciano, M. et al. Evolutionary conserved longevity genes and human cognitive abilities in elderly cohorts. Eur J Hum Genet 20, 341–347 (2012). https://doi.org/10.1038/ejhg.2011.201
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