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Phenotypic and genetic analysis of cognitive performance in Major Depressive Disorder in the Generation Scotland: Scottish Family Health Study.

ABSTRACT: Lower performances in cognitive ability in individuals with Major Depressive Disorder (MDD) have been observed on multiple occasions. Understanding cognitive performance in MDD could provide a wider insight in the aetiology of MDD as a whole. Using a large, well characterised cohort (N?=?7012), we tested for: differences in cognitive performance by MDD status and a gene (single SNP or polygenic score) by MDD interaction effect on cognitive performance. Linear regression was used to assess the association between cognitive performance and MDD status in a case-control, single-episode-recurrent MDD and control-recurrent MDD study design. Test scores on verbal declarative memory, executive functioning, vocabulary, and processing speed were examined. Cognitive performance measures showing a significant difference between groups were subsequently analysed for genetic associations. Those with recurrent MDD have lower processing speed versus controls and single-episode MDD (??=?-2.44, p?=?3.6?×?10-04; ??=?-2.86, p?=?1.8?×?10-03, respectively). There were significantly higher vocabulary scores in MDD cases versus controls (??=?0.79, p?=?2.0?×?10-06), and for recurrent MDD versus controls (??=?0.95, p?=?5.8?×?10-05). Observed differences could not be linked to significant single-locus associations. Polygenic scores created from a processing speed meta-analysis GWAS explained 1% of variation in processing speed performance in the single-episode versus recurrent MDD study (p?=?1.7?×?10-03) and 0.5% of variation in the control versus recurrent MDD study (p?=?1.6?×?10-10). Individuals with recurrent MDD showed lower processing speed and executive function while showing higher vocabulary performance. Within MDD, persons with recurrent episodes show lower processing speed and executive function scores relative to individuals experiencing a single episode.

SUBMITTER: Meijsen JJ

PROVIDER: S-EPMC5847617 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Phenotypic and genetic analysis of cognitive performance in Major Depressive Disorder in the Generation Scotland: Scottish Family Health Study.

Meijsen Joeri J JJ Campbell Archie A Hayward Caroline C Porteous David J DJ Deary Ian J IJ Marioni Riccardo E RE Nicodemus Kristin K KK

Translational psychiatry 20180313 1

Lower performances in cognitive ability in individuals with Major Depressive Disorder (MDD) have been observed on multiple occasions. Understanding cognitive performance in MDD could provide a wider insight in the aetiology of MDD as a whole. Using a large, well characterised cohort (N = 7012), we tested for: differences in cognitive performance by MDD status and a gene (single SNP or polygenic score) by MDD interaction effect on cognitive performance. Linear regression was used to assess the as ...[more]

PMID: 29531327

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Project description:The heritability of Major Depressive Disorder (MDD) has been estimated at 37% based largely on twin studies that rely on contested assumptions. More recently, the heritability of MDD has been estimated on large populations from registries such as the Swedish, Finnish, and Chinese cohorts. Family-based designs utilise a number of different relationships and provide an alternative means of estimating heritability. Generation Scotland: Scottish Family Health Study (GS:SFHS) is a large (n = 20,198), family-based population study designed to identify the genetic determinants of common diseases, including Major Depressive Disorder. Two thousand seven hundred and six individuals were SCID diagnosed with MDD, 13.5% of the cohort, from which we inferred a population prevalence of 12.2% (95% credible interval: 11.4% to 13.1%). Increased risk of MDD was associated with being female, unemployed due to a disability, current smokers, former drinkers, and living in areas of greater social deprivation. The heritability of MDD in GS:SFHS was between 28% and 44%, estimated from a pedigree model. The genetic correlation of MDD between sexes, age of onset, and illness course were examined and showed strong genetic correlations. The genetic correlation between males and females with MDD was 0.75 (0.43 to 0.99); between earlier (≤ age 40) and later (> age 40) onset was 0.85 (0.66 to 0.98); and between single and recurrent episodic illness course was 0.87 (0.72 to 0.98). We found that the heritability of recurrent MDD illness course was significantly greater than the heritability of single MDD illness course. The study confirms a moderate genetic contribution to depression, with a small contribution of the common family environment (variance proportion = 0.07, CI: 0.01 to 0.15), and supports the relationship of MDD with previously identified risk factors. This study did not find robust support for genetic differences in MDD due to sex, age of onset, or illness course. However, we found an intriguing difference in heritability between recurrent and single MDD illness course. These findings establish GS:SFHS as a valuable cohort for the genetic investigation of MDD.

Project description:BackgroundCognitive dysfunction and brain structural connectivity alterations have been observed in major depressive disorder (MDD). However, little is known about their interrelation. The present study follows a network approach to evaluate alterations in cognition-related brain structural networks.MethodsCognitive performance of n = 805 healthy and n = 679 acutely depressed or remitted individuals was assessed using 14 cognitive tests aggregated into cognitive factors. The structural connectome was reconstructed from structural and diffusion-weighted magnetic resonance imaging. Associations between global connectivity strength and cognitive factors were established using linear regressions. Network-based statistics were applied to identify subnetworks of connections underlying these global-level associations. In exploratory analyses, effects of depression were assessed by evaluating remission status-related group differences in subnetwork-specific connectivity. Partial correlations were employed to directly test the complete triad of cognitive factors, depressive symptom severity, and subnetwork-specific connectivity strength.ResultsAll cognitive factors were associated with global connectivity strength. For each cognitive factor, network-based statistics identified a subnetwork of connections, revealing, for example, a subnetwork positively associated with processing speed. Within that subnetwork, acutely depressed patients showed significantly reduced connectivity strength compared to healthy controls. Moreover, connectivity strength in that subnetwork was associated to current depressive symptom severity independent of the previous disease course.ConclusionsOur study is the first to identify cognition-related structural brain networks in MDD patients, thereby revealing associations between cognitive deficits, depressive symptoms, and reduced structural connectivity. This supports the hypothesis that structural connectome alterations may mediate the association of cognitive deficits and depression severity.

Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Project description:ImportanceFindings of cognitive impairment in major depressive disorder (MDD), including remitted MDD, raise the question whether impaired cognition is part of preexisting vulnerability rather than a consequence of MDD or its treatment. To our knowledge, no meta-analyses have been published on cognitive impairment in first-degree relatives of individuals with MDD.ObjectiveTo compare cognitive performance between individuals with and without family history of MDD.Data sourcesMedline/PubMed, PsycINFO, and Embase using combinations of search terms for depression, first-degree relatives, and cognition from January 1, 1980, to July 15, 2018.Study selectionOriginal articles that reported data on cognition in first-degree relatives of individuals with MDD compared with controls with no family history of major mental illness.Data extraction and synthesisMeans and SDs were extracted, and standardized mean differences (SMD) between relatives and controls were calculated for each measure of cognitive performance. The relative-control differences in overall cognition and in specific cognitive domains were synthesized in random-effects meta-analyses with robust variance estimation that allows including multiple correlated measures of cognition within each study. Heterogeneity was quantified with τ2. Publication bias was assessed with funnel plots and Egger intercept.Main outcomes and measuresPerformance on cognitive tests.ResultsAcross 284 measures of cognition in 54 nonoverlapping samples including 3246 relatives of people with MDD (mean age 15.38 years, 57.68% females) and 5222 controls (mean age 14.70 years, 55.93% females), relatives of people with MDD performed worse than controls across all measures of cognition (SMD = -0.19; 95% CI, -0.27 to -0.11; P < .001). Domain-specific meta-analyses showed similar size of relative-control difference in most domains of cognition, including Full-Scale IQ (SMD = -0.19), verbal intelligence (SMD = -0.29), perceptual intelligence (SMD = -0.23), memory (SMD = -0.20), academic performance (SMD = -0.40), and language (SMD = -0.29). Study characteristics were not significantly associated with observed between-group differences. There was no evidence of publication bias.Conclusions and relevanceA general impairment in cognition is a feature of familial disposition for MDD. Cognition may contribute to early identification of risk for depression and may be examined as potential target for early intervention.

Dataset Information

Phenotypic and genetic analysis of cognitive performance in Major Depressive Disorder in the Generation Scotland: Scottish Family Health Study.

Publications

Phenotypic and genetic analysis of cognitive performance in Major Depressive Disorder in the Generation Scotland: Scottish Family Health Study.

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