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Functional Gene Group Analysis Reveals a Role of Synaptic Heterotrimeric G Proteins in Cognitive Ability
Authors:Dina Ruano  Beate Glaser  L. Niels Cornelisse  David M. Evans  Nicolas J. Timpson  Peter Heutink  Danielle Posthuma
Affiliation:1 Department of Functional Genomics, Neuroscience Campus Amsterdam VU University, 1081 HV Amsterdam, The Netherlands
2 Department of Molecular & Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam VU University, 1081 HV Amsterdam, The Netherlands
3 Department of Medical Genomics, VU Medical Center, Neuroscience Campus Amsterdam VU University, 1081 HV Amsterdam, The Netherlands
4 MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol BS8 2BN, UK
5 Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
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 (PEMP = 1.9 × 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.
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