title: Functional gene group analysis reveals a role of synaptic heterotrimeric G proteins in cognitive ability.
abstract: Although cognitive ability is a highly heritable complex trait, only a few genes have been identified, explaining relatively low proportions of the observed trait variation. This implies that hundreds of genes of small effect may be of importance for cognitive ability. We applied an innovative method in which we tested for the effect of groups of genes defined according to cellular function (functional gene group analysis). Using an initial sample of 627 subjects, this functional gene group analysis detected that synaptic heterotrimeric guanine nucleotide binding proteins (G proteins) play an important role in cognitive ability (P(EMP) = 1.9 x 10(-4)). The association with heterotrimeric G proteins was validated in an independent population sample of 1507 subjects. Heterotrimeric G proteins are central relay factors between the activation of plasma membrane receptors by extracellular ligands and the cellular responses that these induce, and they can be considered a point of convergence, or a "signaling bottleneck." Although alterations in synaptic signaling processes may not be the exclusive explanation for the association of heterotrimeric G proteins with cognitive ability, such alterations may prominently affect the properties of neuronal networks in the brain in such a manner that impaired cognitive ability and lower intelligence are observed. The reported association of synaptic heterotrimeric G proteins with cognitive ability clearly points to a new direction in the study of the genetic basis of cognitive ability.
authors.affiliation: Department of Medical Genomics, VU Medical Center, Neuroscience Campus Amsterdam VU University, Amsterdam, The Netherlands.
authors.forename: Dina
authors.initials: D
authors.lastname: Ruano
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: Beate
authors.initials: B
authors.lastname: Glaser
authors.forename: Esther S
authors.initials: ES
authors.lastname: Lips
authors.forename: L Niels
authors.initials: LN
authors.lastname: Cornelisse
authors.forename: Arthur P H
authors.initials: AP
authors.lastname: de Jong
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.forename: Matthijs
authors.initials: M
authors.lastname: Verhage
authors.forename: Danielle
authors.initials: D
authors.lastname: Posthuma
mesh_terms: D000293:Adolescent; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics; D002648:Child; D003071:Cognition; D030541:Databases, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007361:Intelligence Tests; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011786:Quality Control; D015203:Reproducibility of Results; D013569:Synapses / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D020962:Heterotrimeric GTP-Binding Proteins