title: Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins.
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.
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: W D
authors.initials: WD
authors.lastname: Hill
authors.affiliation: 1] Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK [2] Medical Genetics Section, The University of Edinburgh Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Western General Hospital Edinburgh, Edinburgh, UK.
authors.forename: G
authors.initials: G
authors.lastname: Davies
authors.affiliation: Genes to Cognition Programme, Centre for Clinical Brain Sciences and Centre for Neuroregeneration The University of Edinburgh, Edinburgh, UK.
authors.forename: L N
authors.initials: LN
authors.lastname: van de Lagemaat
authors.affiliation: 1] Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway [2] Dr E. Martens Research Group for Biological Psychiatry, Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Christoforou
authors.affiliation: 1] Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK [2] Medical Genetics Section, The University of Edinburgh Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Western General Hospital Edinburgh, Edinburgh, UK [3] Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: R E
authors.initials: RE
authors.lastname: Marioni
authors.affiliation: 1] Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway [2] Dr E. Martens Research Group for Biological Psychiatry, Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: C P D
authors.initials: CP
authors.lastname: Fernandes
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Liewald
authors.affiliation: Genes to Cognition Programme, Centre for Clinical Brain Sciences and Centre for Neuroregeneration The University of Edinburgh, Edinburgh, UK.
authors.forename: M D R
authors.initials: MD
authors.lastname: Croning
authors.affiliation: Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Payton
authors.affiliation: Public Health Nutrition Research Group Section of Population Health, University of Aberdeen, Aberdeen, UK.
authors.forename: L C A
authors.initials: LC
authors.lastname: Craig
authors.affiliation: Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: L J
authors.initials: LJ
authors.lastname: Whalley
authors.affiliation: Centre for Clinical and Cognitive Neurosciences, Institute Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Horan
authors.affiliation: Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
authors.forename: W
authors.initials: W
authors.lastname: Ollier
authors.affiliation: Queensland Institute of Medical Research, Brisbane, QLD, Australia.
authors.forename: N K
authors.initials: NK
authors.lastname: Hansell
authors.affiliation: Queensland Institute of Medical Research, Brisbane, QLD, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Wright
authors.affiliation: Queensland Institute of Medical Research, Brisbane, QLD, Australia.
authors.forename: N G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Queensland Institute of Medical Research, Brisbane, QLD, Australia.
authors.forename: G W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: 1] Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway [2] Dr E. Martens Research Group for Biological Psychiatry, Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: V M
authors.initials: VM
authors.lastname: Steen
authors.affiliation: 1] Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway [2] Dr E. Martens Research Group for Biological Psychiatry, Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Le Hellard
authors.affiliation: 1] Department of Psychology, University of Oslo, Oslo, Norway [2] KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Espeseth
authors.affiliation: 1] Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway [2] Kavli Research Centre for Aging and Dementia, Haraldplass Hospital, Bergen, Norway.
authors.forename: A J
authors.initials: AJ
authors.lastname: Lundervold
authors.affiliation: Department of Psychology, University of Oslo, Oslo, Norway.
authors.forename: I
authors.initials: I
authors.lastname: Reinvang
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: Centre for Clinical and Cognitive Neurosciences, Institute Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.
authors.forename: N
authors.initials: N
authors.lastname: Pendleton
authors.affiliation: Genes to Cognition Programme, Centre for Clinical Brain Sciences and Centre for Neuroregeneration The University of Edinburgh, Edinburgh, UK.
authors.forename: S G N
authors.initials: SG
authors.lastname: Grant
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: T C
authors.identifier: 0000000211539007
authors.initials: TC
authors.lastname: Bates
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: I J
authors.initials: IJ
authors.lastname: Deary
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D003071:Cognition / Q000145:classification / Q000502:physiology*; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D051528:Guanylate Kinases / Q000235:genetics*; D006801:Humans; D007360:Intelligence / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D040901:Proteomics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D051528:Guanylate Kinases