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Evolutionary conserved longevity genes and human cognitive abilities in elderly cohorts.

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.

SUBMITTER: Lopez LM

PROVIDER: S-EPMC3283186 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Evolutionary conserved longevity genes and human cognitive abilities in elderly cohorts.

Lopez Lorna M LM Harris Sarah E SE Luciano Michelle M Liewald Dave D Davies Gail G Gow Alan J AJ Tenesa Albert A Payton Antony A Ke Xiayi X Whalley Lawrence J LJ Fox Helen H Haggerty Paul P Ollier William W Pickles Andrew A Porteous David J DJ Horan Michael A MA Pendleton Neil N Starr John M JM Deary Ian J IJ

European journal of human genetics : EJHG 20111102 3

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 gen ...[more]

PMID: 22045296

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Project description:Twin research has supported the concept of intelligence (general cognitive ability, g) by showing that genetic correlations between diverse tests of verbal and nonverbal cognitive abilities are greater than 0.50. That is, most of the genes that affect cognitive abilities are highly pleiotropic in the sense that genes that affect one cognitive ability affect all cognitive abilities. The impact of this finding may have been blunted because it depends on the validity of the twin method. Although the assumptions of the twin method have survived indirect tests, it is now possible to test findings from the twin method directly using DNA alone in samples of unrelated individuals, without the assumptions of the twin method. We applied this DNA method, implemented in a software package called Genome-wide Complex Trait Analysis (GCTA), to estimate genetic variance and covariance for two verbal tests and two nonverbal tests using 1.7 million DNA markers genotyped on 2500 unrelated children at age 12; 1900 children also had cognitive data and DNA at age 7. Because each of these individuals is one member of a twin pair, we were able to compare GCTA estimates directly to twin study estimates using the same measures in the same sample. At age 12, GCTA confirmed the results of twin research in showing substantial genetic covariance between verbal and nonverbal composites. The GCTA genetic correlation at age 12 was 1.0 (SE = 0.32), not significantly different from the twin study estimate of 0.60 (SE = 0.09). At age 7, the genetic correlations were 0.31 (SE =0.32) from GCTA and 0.71 (SE = 0.15).from twin analysis. The results from the larger sample and stronger measures at age 12 confirm the twin study results that the genetic architecture of intelligence is driven by pleiotropic effects on diverse cognitive abilities. However, the results at age 7 and the large standard errors of GCTA bivariate genetic correlations suggest the need for further research with larger samples.

Project description:BackgroundScales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration.ResultsWe defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases (P< 2× 10-3). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height (P< 6× 10-4), and estimated bone mineral density (eBMD, P< 2× 10-5). Zebrafish mutants of two human orthologues that were robustly associated with height (COL11A2, P=6× 10-24) or eBMD (SPP1, P=6× 10-20) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2Y228X/Y228X mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1P160X/P160X mutants predominantly showed mineralisation defects.ConclusionWe show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease.

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Evolutionary conserved longevity genes and human cognitive abilities in elderly cohorts.

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Evolutionary conserved longevity genes and human cognitive abilities in elderly cohorts.

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