Gene-Based Analysis of Regionally Enriched Cortical Genes in GWAS Data Sets of Cognitive Traits and Psychiatric Disorders

Abstract

BackgroundDespite 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.Principal FindingsAt 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.ConclusionOur 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.

RETRACTED: Identification of gene ontologies linked to prefrontal–hippocampal functional coupling in the human brain

“…a phenotype of interest tend to significantly aggregate within specific biologically based "gene sets." As an adjunct to established GWA studies and candidate gene approaches, GSEA has successfully identified genes sets with established risk genes for complex diseases such as lung cancer, Parkinson's disease, and psychiatric disorders, yielding insight into plausible biological processes and molecular mechanisms warranting further investigation (24)(25)(26).…”

“…To map individual SNPs to genes and derive a genelevel summary score, we used the LDsnpR package, previously implemented by Ersland et al (26,90). The LDsnpR package was used to assign SNPs to genes using chromosomal position and linkage disequilibrium information from Human Emsembl 66 release and the CEU (Utah residents with ancestry from northern and western Europe) sample from HapMap Phase II.…”

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

“…In humans, genetic association of RORB with bipolar disorder and cognitive functioning has been suggested. 24,25 Mild-tomoderate neurocognitive and behavioral abnormalities mentioned in all patients with RORB dysfunction support that RORB may play a key role in neurocognitive processes.…”

“…Standard karyotype on 50 mitoses revealed a complex mosaic chromosomes imbalances composed of a small supernumerary ring marker chromosome in 25 mitoses (50%), a derivative chromosome 9 from a t(9;21) translocation in one mitose (2%), and a normal 46,XX population in 24 mitoses (48%): mos 47,XX,+r [20]/46,XX, − 21,+der (9)t(9;21) [5]/46,XX [25]. In addition, aCGH analysis revealed a homogeneous 8.5-Mb deletion of the long arm of chromosome 9 (chr9:g.70984481_79549501del), containing 47 genes including RORB and a mosaic gain involving the whole short arm of chromosome 9 ( Figure 2a).…”

An overview of mice models: a key for understanding subtypes of mania

“…On this question, Ersland et al found similar functional annotations for homologous genes in humans and rats in frontal and temporal areas which could give functional clues to cellular communication mechanisms, intracellular signaling cascades, signal transduction, emryogenesis, and neurogenesis, potentially associated with cognitive dysfunction in mania (Ersland, et al 2012;Le-Niculescu, et al 2009). For example, changes in the expression of the brainderived neurotrophic factor (Bdnf) in mice are associated with deterioration in work memory and present dorsolateral correlation.…”