Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins

W. D. Hill, G. Davies, L. N. Van De Lagemaat, A. Christoforou, R. E. Marioni, C. P D Fernandes, D. C. Liewald, M. D R Croning, A. Payton, L. C A Craig, L. J. Whalley, M. Horan, W. Ollier, N. K. Hansell, M. J. Wright, N. G. Martin, G. W. Montgomery, V. M. Steen, S. Le Hellard, T. EspesethA. J. Lundervold, I. Reinvang, J. M. Starr, N. Pendleton, S. G N Grant, T. C. Bates, I. J. Deary*

*Corresponding author for this work

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P = 0.002. Replication was sought in two additional cohorts (N = 670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.

Original languageEnglish
Article numbere341
Pages (from-to)1-8
Number of pages8
JournalTranslational Psychiatry
Volume4
Early online date7 Jan 2014
DOIs
Publication statusPublished - 2014

Keywords

  • GWAS
  • Intelligence
  • NMDA-RC
  • Pathway analysis
  • Synapse

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry
  • Cellular and Molecular Neuroscience
  • Medicine(all)

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    Hill, W. D., Davies, G., Van De Lagemaat, L. N., Christoforou, A., Marioni, R. E., Fernandes, C. P. D., Liewald, D. C., Croning, M. D. R., Payton, A., Craig, L. C. A., Whalley, L. J., Horan, M., Ollier, W., Hansell, N. K., Wright, M. J., Martin, N. G., Montgomery, G. W., Steen, V. M., Le Hellard, S., ... Deary, I. J. (2014). Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins. Translational Psychiatry, 4, 1-8. [e341]. https://doi.org/10.1038/tp.2013.114