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Gene-based analysis of regionally enriched cortical genes in GWAS data sets of cognitive traits and psychiatric disorders.

Ersland KM, Christoforou A, Stansberg C, Espeseth T, Mattheisen M, Mattingsdal M, Hardarson GA, Hansen T, Fernandes CP, Giddaluru S, Breuer R, Strohmaier J, Djurovic S, Nöthen MM, Rietschel M, Lundervold AJ, Werge T, Cichon S, Andreassen OA, Reinvang I, Steen VM, Le Hellard S - PLoS ONE (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Dr E Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

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.

Principal findings: 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.

Conclusion: 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.

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Related in: MedlinePlus

Schematic overview of the method.SNP markers from GWAS data were assigned to single genes in a process termed “gene binning”, by implementing a novel LD-based tool (LDsnpR, Christoforou et al. under revision). Modified Sidak's P-values were extracted for each gene (“gene bin”) in the GWAS data sets. Single gene-based analysis of the differentially expressed cortical genes was performed by extracting the modified Sidak's P-values for the candidate genes from the NCNG GWAS. Gene set-based analysis of the differentially expressed cortical genes was performed by extraction of the modified Sidak's P-values, followed by GSEA of GWAS data on cognition, psychiatric disorders and non-psychiatric phenotypes. GSEA: Gene set enrichment analysis, GWAS: Genome-wide association study.
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pone-0031687-g001: Schematic overview of the method.SNP markers from GWAS data were assigned to single genes in a process termed “gene binning”, by implementing a novel LD-based tool (LDsnpR, Christoforou et al. under revision). Modified Sidak's P-values were extracted for each gene (“gene bin”) in the GWAS data sets. Single gene-based analysis of the differentially expressed cortical genes was performed by extracting the modified Sidak's P-values for the candidate genes from the NCNG GWAS. Gene set-based analysis of the differentially expressed cortical genes was performed by extraction of the modified Sidak's P-values, followed by GSEA of GWAS data on cognition, psychiatric disorders and non-psychiatric phenotypes. GSEA: Gene set enrichment analysis, GWAS: Genome-wide association study.

Mentions: The candidate genes were treated as four separate gene sets. Gene set 1: All cortex region enriched genes (FMCx, TCx and OCx, n = 62), Gene set 2: FMCx enriched genes (n = 29), Gene set 3: TCx enriched genes (n = 22) and Gene set 4: OCx enriched genes (n = 11) (Table 1–3). The GSEA 2.0 programme (http://www.broadinstitute.org/gsea/index.jsp) [32] was used to analyse the distribution of the candidate genes in the pre-ranked lists of genes from the different GWAS data sets. The gene sets were analysed in the ranked files, using weighted enrichment statistics (p = 1) and 1,500 permutations. The analysis was repeated three times to ensure consistency of results, and the false discovery rate (FDR) q-values were extracted for each trait/GWAS. See Figure 1 for schematic overview of the different steps in the procedure.


Gene-based analysis of regionally enriched cortical genes in GWAS data sets of cognitive traits and psychiatric disorders.

Ersland KM, Christoforou A, Stansberg C, Espeseth T, Mattheisen M, Mattingsdal M, Hardarson GA, Hansen T, Fernandes CP, Giddaluru S, Breuer R, Strohmaier J, Djurovic S, Nöthen MM, Rietschel M, Lundervold AJ, Werge T, Cichon S, Andreassen OA, Reinvang I, Steen VM, Le Hellard S - PLoS ONE (2012)

Schematic overview of the method.SNP markers from GWAS data were assigned to single genes in a process termed “gene binning”, by implementing a novel LD-based tool (LDsnpR, Christoforou et al. under revision). Modified Sidak's P-values were extracted for each gene (“gene bin”) in the GWAS data sets. Single gene-based analysis of the differentially expressed cortical genes was performed by extracting the modified Sidak's P-values for the candidate genes from the NCNG GWAS. Gene set-based analysis of the differentially expressed cortical genes was performed by extraction of the modified Sidak's P-values, followed by GSEA of GWAS data on cognition, psychiatric disorders and non-psychiatric phenotypes. GSEA: Gene set enrichment analysis, GWAS: Genome-wide association study.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3285182&req=5

pone-0031687-g001: Schematic overview of the method.SNP markers from GWAS data were assigned to single genes in a process termed “gene binning”, by implementing a novel LD-based tool (LDsnpR, Christoforou et al. under revision). Modified Sidak's P-values were extracted for each gene (“gene bin”) in the GWAS data sets. Single gene-based analysis of the differentially expressed cortical genes was performed by extracting the modified Sidak's P-values for the candidate genes from the NCNG GWAS. Gene set-based analysis of the differentially expressed cortical genes was performed by extraction of the modified Sidak's P-values, followed by GSEA of GWAS data on cognition, psychiatric disorders and non-psychiatric phenotypes. GSEA: Gene set enrichment analysis, GWAS: Genome-wide association study.
Mentions: The candidate genes were treated as four separate gene sets. Gene set 1: All cortex region enriched genes (FMCx, TCx and OCx, n = 62), Gene set 2: FMCx enriched genes (n = 29), Gene set 3: TCx enriched genes (n = 22) and Gene set 4: OCx enriched genes (n = 11) (Table 1–3). The GSEA 2.0 programme (http://www.broadinstitute.org/gsea/index.jsp) [32] was used to analyse the distribution of the candidate genes in the pre-ranked lists of genes from the different GWAS data sets. The gene sets were analysed in the ranked files, using weighted enrichment statistics (p = 1) and 1,500 permutations. The analysis was repeated three times to ensure consistency of results, and the false discovery rate (FDR) q-values were extracted for each trait/GWAS. See Figure 1 for schematic overview of the different steps in the procedure.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Dr E Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

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.

Principal findings: 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus