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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. 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.

SUBMITTER: Ersland KM

PROVIDER: S-EPMC3285182 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

Ersland Kari M KM Christoforou Andrea A Stansberg Christine C Espeseth Thomas T Mattheisen Manuel M Mattingsdal Morten M Hardarson Gudmundur A GA Hansen Thomas T Fernandes Carla P D CP Giddaluru Sudheer S Breuer René R Strohmaier Jana J Djurovic Srdjan S Nöthen Markus M MM Rietschel Marcella M Lundervold Astri J AJ Werge Thomas T Cichon Sven S Andreassen Ole A OA Reinvang Ivar I Steen Vidar M VM Le Hellard Stephanie S

PloS one 20120222 2

<h4>Background</h4>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 ...[more]

PMID: 22384057

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Project description:Background: Epidemiological research has reported that attention-deficit hyperactivity disorder (ADHD), anxiety, bipolar disorder (BD), schizophrenia (SCZ), and unipolar depression (UD) are multimorbid conditions that are typically accompanied by cognitive advantages or deficits, suggesting that common biological mechanisms may underlie these phenotypes. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with psychiatric disorders and cognitive functioning. However, the mechanisms by which these SNPs contribute to multimorbidities amongst psychiatric and cognitive phenotypes remains largely unknown. Objective: To identify shared regulatory mechanisms amongst multimorbid psychiatric disorders and cognitive functioning. Methods: We integrated data on 3D genome organization, expression quantitative trait loci (eQTLs), and pathway analyses to identify shared and specific regulatory impacts of 2,893 GWAS SNPs (p < 1 × 10-6) associated with ADHD, anxiety, BD, SCZ, UD, and cognitive functioning on genes and biological pathways. Drug-gene interaction analysis was performed to identify potential pharmacological impacts on these genes and pathways. Results: The analysis revealed 33 genes and 62 pathways that were commonly affected by tissue-specific gene regulatory interactions associated with all six phenotypes despite there being no common SNPs in our original dataset. The analysis of brain-specific regulatory connections revealed similar patterns at eQTL and eGene levels, but no pathways shared by all six phenotypes. Instead, pairwise overlaps and individualized pathways were identified for psychiatric and cognitive phenotypes in brain tissues. Conclusions: This study offers insight into the shared genes and biological pathways that are affected by tissue-specific regulatory impacts resulting from psychiatric- and cognition-associated genetic variants. These results provide limited support for the "p-factor" hypothesis for psychiatric disorders and potential mechanisms that explain drug side-effects. Our results highlight key biological pathways for development of therapies that target single or multiple psychiatric and cognitive phenotypes.

Project description:Integrating findings from genome-wide association studies with molecular datasets can develop insight into the underlying functional mechanisms responsible for trait-associated genetic variants. We have applied the principles of Mendelian randomization (MR) to investigate whether brain-derived gene expression (n = 1194) may be responsible for mediating the effect of genetic variants on eight cognitive and psychological outcomes (attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, bipolar disorder, depression, intelligence, insomnia, neuroticism and schizophrenia). Transcriptome-wide analyses identified 83 genes associated with at least one outcome (PBonferroni < 6.72 × 10-6), with multiple-trait colocalization also implicating changes to brain-derived DNA methylation at nine of these loci. Comparing effects between outcomes identified evidence of enrichment which may reflect putative causal relationships, such as an inverse relationship between genetic liability towards schizophrenia risk and cognitive ability in later life. Repeating these analyses in whole blood (n = 31 684), we replicated 58.2% of brain-derived effects (based on P < 0.05). Finally, we undertook phenome-wide evaluations at associated loci to investigate pleiotropic effects with 700 complex traits. This highlighted pleiotropic loci such as FURIN (initially implicated in schizophrenia risk (P = 1.05 × 10-7)) which had evidence of an effect on 28 other outcomes, as well as genes which may have a more specific role in disease pathogenesis (e.g. SLC12A5 which only provided evidence of an effect on depression (P = 7.13 × 10-10)). Our results support the utility of whole blood as a valuable proxy for informing initial target identification but also suggest that gene discovery in a tissue-specific manner may be more informative. Finally, non-pleiotropic loci highlighted by our study may be of use for therapeutic translational endeavours.

Project description:BackgroundAutomatic biases, such as attentional biases and avoidance and interpretative biases, have been purported to be responsible for several psychiatric disorders. Gamification has been considered for cognitive bias modification, mainly to address the core issues of diminishing motivation to train over time, as bias modification intervention tasks tend to be highly repetitive. While a prior review has suggested how gamification strategies could be applied to such tasks, there remains a lack of systematic evaluation of gamified cognitive bias modification interventions in the literature.ObjectiveThe objective of this review is to understand the overall effectiveness of a gamified approach for cognitive bias modification and inform future research that seeks to integrate gamification technologies into existing conventional bias modification interventions.MethodsTo identify the relevant articles for our review, the following search terminologies were used: ("cognitive bias" OR "attention bias" OR "interpret* bias" OR "approach bias" OR "avoidance bias") AND ("training" OR "modification" OR "practice" OR "therapy") AND ("gamification" OR "game elements" OR "game" OR "gaming" OR "game mechanics"). PubMed, MEDLINE, PsycINFO, and Scopus databases were searched systematically for articles published after 2000. Articles were included if they described a gamified cognitive bias modification task and included participants with underlying psychopathological symptoms. Data were systematically extracted from the identified articles, and a qualitative synthesis was performed.ResultsFour studies evaluated gamified cognitive bias modification interventions. Two studies included participants with anxiety symptoms, one with affective symptoms, and one with alcohol problems. The conventional visual probe task paradigm was used in 3 studies, and the attentional visual search task paradigm was used in the last study. We found gaming elements incorporated to include that of animations, sounds, feedback, and a point-scoring system for response time and difficulty. Of the 4 identified studies, only 2 reported their gamified interventions to be effective.ConclusionsOur review is the first to systematically synthesize the evidence for gamified cognitive bias modification interventions. The results arising from our review should be considered in the future design and conceptualization of gamified cognitive bias modification interventions.International registered report identifier (irrid)RR2-10.2196/10154.

Dataset Information

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

Publications

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

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