Dataset Information

CACNA1C rs1006737, Threatening Life Events, and Gene-Environment Interaction Predict Major Depressive Disorder.

ABSTRACT: Introduction:CACNA1C rs1006737 is a novel variant in discovery of replicable associations in major depressive disorder (MDD). However, there have been no specific studies considered effect of environmental pathogens to date examining its clinical significance. In this study we investigated the interaction effect between CACNA1C rs1006737 polymorphism and threatening life events (TLEs) in MDD and carried out a meta-analysis of published findings. Methods:A total of 1,177 consecutive participants were genotyped. Information on exposure to TLEs, socio-demographic data, and history of psychological problems among first-degree relatives was collected. MDD was diagnosed according to the Chinese version of the 24-item Hamilton Rating Scale for Depression. Results:There was a significant interaction effect between CACNA1C rs1006737 polymorphism and TLEs in MDD. A dose-response relationship was found between CACNA1C rs1006737 genotypes and TLEs in MDD. The results of the meta-analysis showed that CACNA1C rs1006737 genotypes interacted with TLEs in MDD. Conclusion:CACNA1C rs1006737 genotype and previous exposure to TLEs interact to influence the risk of developing MDD. We propose that CACNA1C rs1006737 may represent a target for novel pharmacological therapies to prevent or treat MDD.

SUBMITTER: Zhao M

PROVIDER: S-EPMC6987424 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

<i>CACNA1C rs1006737</i>, Threatening Life Events, and Gene-Environment Interaction Predict Major Depressive Disorder.

Zhao Mingzhe M Yang Jiarun J Qiu Xiaohui X Yang Xiuxian X Qiao Zhengxue Z Song Xuejia X Wang Lin L Zhao Erying E Yang Yanjie Y Cao Depin D

Frontiers in psychiatry 20200122

<h4>Introduction</h4><i>CACNA1C rs1006737</i> is a novel variant in discovery of replicable associations in major depressive disorder (MDD). However, there have been no specific studies considered effect of environmental pathogens to date examining its clinical significance. In this study we investigated the interaction effect between <i>CACNA1C rs1006737</i> polymorphism and threatening life events (TLEs) in MDD and carried out a meta-analysis of published findings.<h4>Methods</h4>A total of 1, ...[more]

PMID: 32038325

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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:BackgroundPanic disorder (PD) is characterized by recurrent panic attacks and higher affection of women as compared to men. The lifetime prevalence of PD is about 2-3% in the general population leading to tremendous distress and disability. Etiologically, genetic and environmental factors, such as stress, contribute to the onset and relapse of PD. In the present study, we investigated epigenome-wide DNA methylation (DNAm) in respond to a cumulative, stress-weighted life events score (wLE) in patients with PD and its boundary to major depressive disorder (MDD), frequently co-occurring with symptoms of PD.MethodsDNAm was assessed by the Illumina HumanMethylation450 BeadChip. In a meta-analytic approach, epigenome-wide DNAm changes in association with wLE were first analyzed in two PD cohorts (with a total sample size of 183 PD patients and 85 healthy controls) and lastly in 102 patients with MDD to identify possible overlapping and opposing effects of wLE on DNAm. Additionally, analysis of differentially methylated regions (DMRs) was conducted to identify regional clusters of association.ResultsTwo CpG-sites presented with p-values below 1 × 10-05 in PD: cg09738429 (p = 6.40 × 10-06, located in an intergenic shore region in next proximity of PYROXD1) and cg03341655 (p = 8.14 × 10-06, located in the exonic region of GFOD2). The association of DNAm at cg03341655 and wLE could be replicated in the independent MDD case sample indicating a diagnosis independent effect. Genes mapping to the top hits were significantly upregulated in brain and top hits have been implicated in the metabolic system. Additionally, two significant DMRs were identified for PD only on chromosome 10 and 18, including CpG-sites which have been reported to be associated with anxiety and other psychiatric phenotypes.ConclusionThis first DNAm analysis in PD reveals first evidence of small but significant DNAm changes in PD in association with cumulative stress-weighted life events. Most of the top associated CpG-sites are located in genes implicated in metabolic processes supporting the hypothesis that environmental stress contributes to health damaging changes by affecting a broad spectrum of systems in the body.

Dataset Information

CACNA1C rs1006737, Threatening Life Events, and Gene-Environment Interaction Predict Major Depressive Disorder.

Publications

<i>CACNA1C rs1006737</i>, Threatening Life Events, and Gene-Environment Interaction Predict Major Depressive Disorder.

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