The genetics of major depression.
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ABSTRACT:
SUBMITTER: Flint J
PROVIDER: S-EPMC3919201 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Depressive disorders (DDs) are one of the most widespread forms of psychiatric pathology. According to the World Health Organization, about 350 million people in the world are affected by this condition. Family and twin studies have demonstrated that the contribution of genetic factors to the risk of the onset of DDs is quite large. Various methodological approaches (analysis of candidate genes, genome-wide association analysis, genome-wide sequencing) have been used, and a large number of the associations between genes and different clinical DD variants and DD subphenotypes have been published. However, in most cases, these associations have not been confirmed in replication studies, and only a small number of genes have been proven to be associated with DD development risk. To ascertain the role of genetic factors in DD pathogenesis, further investigations of the relevant conditions are required. Special consideration should be given to the polygenic characteristics noted in whole-genome studies of the heritability of the disorder without a pronounced effect of the major gene. These observations accentuate the relevance of the analysis of gene-interaction roles in DD development and progression. It is important that association studies of the inherited variants of the genome should be supported by analysis of dynamic changes during DD progression. Epigenetic changes that cause modifications of a gene's functional state without changing its coding sequence are of primary interest. However, the opportunities for studying changes in the epigenome, transcriptome, and proteome during DD are limited by the nature of the disease and the need for brain tissue analysis, which is possible only postmortem. Therefore, any association studies between DD pathogenesis and epigenetic factors must be supplemented through the use of different animal models of depression. A threefold approach comprising the combination of gene association studies, assessment of the epigenetic state in DD patients, and analysis of different "omic" changes in animal depression models will make it possible to evaluate the contribution of genetic, epigenetic, and environmental factors to the development of different forms of depression and to help develop ways to decrease the risk of depression and improve the treatment of DD.
| S-EPMC6065213 | biostudies-literature
Project description:Efforts to unlock the biology of major depressive disorder (MDD) are proceeding on multiple fronts. In this article, the authors review the current understanding of epidemiological evidence for a heritable component to MDD risk, as well as recent advances in linkage, candidate gene, and genome-wide association analyses of MDD and related disease subtypes and endophenotypes. While monoamine signaling has preoccupied the bulk of scientific investigation to date, nontraditional gene candidates such as PCLO and GRM7 are now emerging and beginning to change the landscape for future human and animal research on depression.
| S-EPMC2824618 | biostudies-literature
Project description:Background: Major Depressive Disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for MDD suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesized that regulatory genomic processes are involved in the pathology of both MDD and suicidality. Methods: Genome-wide patterns of DNA methylation were assessed in depressed MDD suicide completers (n=20) and compared to non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focussed on identifying differentially methylated regions (DMRs) associated with suicidal depression, and epigenetic variation was explored in the context of polygenic risk scores for major depression and MDD suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed MDD suicide completers and polygenic burden for MDD and MDD suicide attempt. Results: We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite-pyrosequencing and replicated in a second set of MDD suicide samples, which is characterized by significant hypomethylation in both cortical brain regions in MDD MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for MDD suicide attempt, but not major depression. MDD suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Conclusions: Our data suggest there are coordinated changes in DNA methylation associated with MDD suicide that may offer novel insights into the molecular pathology associated with depressed MDD suicide completers.
2016-11-01 | GSE88890 | GEO
Project description:Major depressive disorder is heritable and a leading cause of disability. Cognitive behavior therapy is an effective treatment for major depression. By quantifying genetic risk scores based on common genetic variants, the aim of this report was to explore the utility of psychiatric and cognitive trait genetic risk scores, for predicting the response of 894 adults with major depressive disorder to cognitive behavior therapy. The participants were recruited in a psychiatric setting, and the primary outcome score was measured using the Montgomery Åsberg Depression Rating Scale-Self Rated. Single-nucleotide polymorphism genotyping arrays were used to calculate the genomic risk scores based on large genetic studies of six phenotypes: major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, intelligence, and educational attainment. Linear mixed-effect models were used to test the relationships between the six genetic risk scores and cognitive behavior therapy outcome. Our analyses yielded one significant interaction effect (B = 0.09, p < 0.001): the autism spectrum disorder genetic risk score correlated with Montgomery Åsberg Depression Rating Scale-Self Rated changes during treatment, and the higher the autism spectrum disorder genetic load, the less the depressive symptoms decreased over time. The genetic risk scores for the other psychiatric and cognitive traits were not related to depressive symptom severity or change over time. Our preliminary results indicated, as expected, that the genomics of the response of patients with major depression to cognitive behavior therapy were complex and that future efforts should aim to maximize sample size and limit subject heterogeneity in order to gain a better understanding of the use of genetic risk factors to predict treatment outcome.
| S-EPMC6477793 | biostudies-literature
Project description:Blood samples taken from healthy controls and patients with major depression were analyzed for differences in microRNA expression. Patients were treated with either electroconvulsive therapy or ketamine and samples were again analyzed to determine if these treatments affected microRNA expression. Baseline microRNA expression profiles were studied to see if they could predict treatment response.
2016-08-31 | GSE81152 | GEO
Project description:To gain insight into the potential role of miRNA in major depressive disorder, in this study we assessed global expression of miRNAs in the ventrolateral prefrontal cortex (PFC) of depressed individuals in comparison to psychiatrically healthy controls. Our screening pointed to miR-1202, a miRNA specific to primates and enriched in the human brain. We validated our findings using quantitative real-time PCR and identified target genes of the differentially expressed miRNAs using bioinformatics analysis. MiR-1202 interacts with and regulates the expression of the metabotropic glutamate receptor 4 (GRM4) gene, and it responds to antidepressant treatment. These results suggest that miR-1202 is associated with the pathophysiology of depression, and is a potential target for novel antidepressant treatments. We assessed the global expression pattern of miRNAs in the ventrolateral PFC of depressed individuals (n = 14) in comparison with psychiatrically healthy controls (n = 11) using the Agilent human miRNA microarrays. Statistical analysis after multiple test correction identified miR-1202 as the most significantly dysregulated miRNA, with levels down-regulated in depressed brains. We validated the microarray miR-1202 findings by qRT-PCR using TaqMan probes, and found consistent results across the two expression analysis methods.
2014-05-30 | E-GEOD-58105 | biostudies-arrayexpress
Project description:To gain insight into the potential role of miRNA in major depressive disorder, in this study we assessed global expression of miRNAs in the ventrolateral prefrontal cortex (PFC) of depressed individuals in comparison to psychiatrically healthy controls. Our screening pointed to miR-1202, a miRNA specific to primates and enriched in the human brain. We validated our findings using quantitative real-time PCR and identified target genes of the differentially expressed miRNAs using bioinformatics analysis. MiR-1202 interacts with and regulates the expression of the metabotropic glutamate receptor 4 (GRM4) gene, and it responds to antidepressant treatment. These results suggest that miR-1202 is associated with the pathophysiology of depression, and is a potential target for novel antidepressant treatments.
2014-05-30 | GSE58105 | GEO
Project description:Several studies have suggested that SSD is a transitory phenomena in the depression spectrum and is thus considered a subtype of depression. However, the pathophysioloy of depression remain largely obscure and studies on SSD are limited. The present study compared the expression profile and made the classification with the leukocytes by using whole-genome cRNA microarrays among drug-free first-episode subjects with SSD, MDD, and healthy controls. We used microarrays to detail the global programme of gene expression to develop blood-based gene expression profiles models for classification of subsyndromal symptomatic depression and major depressive disorder The present study compared the expression profile and made the classification with the leukocytes by using whole-genome cRNA microarrays among drug-free first-episode subjects with SSD, MDD, and matched controls (8 subjects in each group). Support vector machines (SVMs) were utilized for training and testing on candidate signature expression profiles from signature selection step.
2012-03-21 | E-GEOD-32280 | biostudies-arrayexpress
Project description:Several studies have suggested that SSD is a transitory phenomena in the depression spectrum and is thus considered a subtype of depression. However, the pathophysioloy of depression remain largely obscure and studies on SSD are limited. The present study compared the expression profile and made the classification with the leukocytes by using whole-genome cRNA microarrays among drug-free first-episode subjects with SSD, MDD, and healthy controls. We used microarrays to detail the global programme of gene expression to develop blood-based gene expression profiles models for classification of subsyndromal symptomatic depression and major depressive disorder
2012-03-21 | GSE32280 | GEO
Project description:BackgroundBoth genetic and environmental factors contribute to risk of depression, but estimates of their relative contributions are limited. Commonalities between clinically-assessed major depressive disorder (MDD) and self-declared depression (SDD) are also unclear.MethodsUsing data from a large Scottish family-based cohort (GS:SFHS, N=19,994), we estimated the genetic and environmental variance components for MDD and SDD. The components representing the genetic effect associated with genome-wide common genetic variants (SNP heritability), the additional pedigree-associated genetic effect and non-genetic effects associated with common environments were estimated in a linear mixed model (LMM).FindingsBoth MDD and SDD had significant contributions from components representing the effect from common genetic variants, the additional genetic effect associated with the pedigree and the common environmental effect shared by couples. The estimate of correlation between SDD and MDD was high (r=1.00, se=0.20) for common-variant-associated genetic effect and lower for the additional genetic effect from the pedigree (r=0.57, se=0.08) and the couple-shared environmental effect (r=0.53, se=0.22).InterpretationBoth genetics and couple-shared environmental effects were major factors influencing liability to depression. SDD may provide a scalable alternative to MDD in studies seeking to identify common risk variants. Rarer variants and environmental effects may however differ substantially according to different definitions of depression.
| S-EPMC5161419 | biostudies-literature