title: Gene-based analysis of regionally enriched cortical genes in GWAS data sets of cognitive traits and psychiatric disorders.
abstract: BACKGROUND
  Despite its estimated high heritability, the genetic architecture leading to differences in cognitive performance remains poorly understood. Different cortical regions play important roles in normal cognitive functioning and impairment. Recently, we reported on sets of regionally enriched genes in three different cortical areas (frontomedial, temporal and occipital cortices) of the adult rat brain. It has been suggested that genes preferentially, or specifically, expressed in one region or organ reflect functional specialisation. Employing a gene-based approach to the analysis, we used the regionally enriched cortical genes to mine a genome-wide association study (GWAS) of the Norwegian Cognitive NeuroGenetics (NCNG) sample of healthy adults for association to nine psychometric tests measures. In addition, we explored GWAS data sets for the serious psychiatric disorders schizophrenia (SCZ) (n = 3 samples) and bipolar affective disorder (BP) (n = 3 samples), to which cognitive impairment is linked.
  
  
  RESULTS
  At the single gene level, the temporal cortex enriched gene RAR-related orphan receptor B (RORB) showed the strongest overall association, namely to a test of verbal intelligence (Vocabulary, P = 7.7E-04). We also applied gene set enrichment analysis (GSEA) to test the candidate genes, as gene sets, for enrichment of association signal in the NCNG GWAS and in GWASs of BP and of SCZ. We found that genes differentially expressed in the temporal cortex showed a significant enrichment of association signal in a test measure of non-verbal intelligence (Reasoning) in the NCNG sample.
  
  
  CONCLUSIONS
  Our gene-based approach suggests that RORB could be involved in verbal intelligence differences, while the genes enriched in the temporal cortex might be important to intellectual functions as measured by a test of reasoning in the healthy population. These findings warrant further replication in independent samples on cognitive traits.
authors.affiliation: Dr E Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Kari M
authors.initials: KM
authors.lastname: Ersland
authors.forename: Andrea
authors.initials: A
authors.lastname: Christoforou
authors.forename: Christine
authors.initials: C
authors.lastname: Stansberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Espeseth
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.forename: Morten
authors.initials: M
authors.lastname: Mattingsdal
authors.forename: Gudmundur A
authors.initials: GA
authors.lastname: Hardarson
authors.forename: Thomas
authors.initials: T
authors.lastname: Hansen
authors.forename: Carla P D
authors.initials: CP
authors.lastname: Fernandes
authors.forename: Sudheer
authors.initials: S
authors.lastname: Giddaluru
authors.forename: René
authors.initials: R
authors.lastname: Breuer
authors.forename: Jana
authors.initials: J
authors.lastname: Strohmaier
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Astri J
authors.initials: AJ
authors.lastname: Lundervold
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.forename: Ivar
authors.initials: I
authors.lastname: Reinvang
authors.forename: Vidar M
authors.initials: VM
authors.lastname: Steen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Le Hellard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000378:metabolism; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics*; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D008875:Middle Aged; D008957:Models, Genetic; D009664:Norway; D009778:Occipital Lobe / Q000473:pathology; D051381:Rats; D012559:Schizophrenia / Q000235:genetics; D013702:Temporal Lobe / Q000473:pathology