Dataset Information

Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts.

ABSTRACT:

Background

Major depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings.

Methods

In this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and duplications, partitioned by length (<100 kb or >100 kb) and other characteristics, and 2) individual rare exonic CNVs and CNV regions.

Results

Patients with MDD carried significantly more short deletions than control subjects (p = .0059) but not long deletions or short or long duplications. The confidence interval for long deletions overlapped with that for short deletions, but long deletions were 70% less frequent genome-wide, reducing the power to detect increased burden. The increased burden of short deletions was primarily in intergenic regions. Short deletions in cases were also modestly enriched for high-confidence enhancer regions. No individual CNV achieved thresholds for suggestive or significant association after genome-wide correction. p values < .01 were observed for 15q11.2 duplications (TUBGCP5, CYFIP1, NIPA1, and NIPA2), deletions in or near PRKN or MSR1, and exonic duplications of ATG5.

Conclusions

The increased burden of short deletions in patients with MDD suggests that rare CNVs increase the risk of MDD by disrupting regulatory regions. Results for longer deletions were less clear, but no large effects were observed for long multigenic CNVs (as seen in schizophrenia and autism). Further studies with larger sample sizes are warranted.

SUBMITTER: Zhang X

PROVIDER: S-EPMC6750266 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts.

Zhang Xianglong X Abdellaoui Abdel A Rucker James J de Jong Simone S Potash James B JB Weissman Myrna M MM Shi Jianxin J Knowles James A JA Pato Carlos C Pato Michele M Sobell Janet J Smit Johannes H JH Hottenga Jouke-Jan JJ de Geus Eco J C EJC Lewis Cathryn M CM Buttenschøn Henriette N HN Craddock Nick N Jones Ian I Jones Lisa L McGuffin Peter P Mors Ole O Owen Michael J MJ Preisig Martin M Rietschel Marcella M Rice John P JP Rivera Margarita M Uher Rudolf R Gejman Pablo V PV Sanders Alan R AR Boomsma Dorret D Penninx Brenda W J H BWJH Breen Gerome G Levinson Douglas F DF

Biological psychiatry 20190313 12

<h4>Background</h4>Major depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings.<h4>Methods</h4>In this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and dupl ...[more]

PMID: 31003785

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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:BackgroundDepression disorders are a leading cause of disability in the world which imposes a significant economic burden on patients and societies The present study aimed to determine the economic burden of Major Depressive Disorder (MDD) on the patients referred to the reference psychiatric single-specialty hospitals in southern Iran in 2020.MethodsThis cross-sectional research is a partial economic evaluation and a cost-of-illness study conducted in southern Iran in 2020. A total of 563 patients were enrolled through the census method, and a researcher-made data collection form was used to gather the required information. The prevalence-based and the bottom-up approaches were also used to collect the cost information and calculate the costs, respectively. The data on direct medical, direct non-medical, and indirect costs were obtained using the information in the patients' medical records and insurance bills as well as their self-reports or those of their companions. To calculate the indirect costs, the human capital approach was used as well.ResultsThe results showed that the annual cost of MDD was $ 2717.41 Purchasing Power Parity (PPP) (USD 2026.13) per patient in 2020. Direct medical costs accounted for the largest share of the costs (73.68%), of which hoteling and regular beds expenses were the highest (57.70% of the total direct medical costs). The shares of direct non-medical and indirect costs were 7.52 and 18.80%, respectively, and the economic burden of the disease in the country was estimated at $7,120,456,596 PPP (USD 5,309,088,699).ConclusionIn general, due to the high prevalence of MDD and the chronicity of the disease, the costs of its treatment can impose a heavy economic burden on the society, healthcare system, insurance system, and the patients themselves. Therefore, it is suggested that health policymakers and managers should take appropriate measures to increase the basic and supplemental insurance coverage of these patients. In addition, in order to reduce the costs, proper and equitable distribution of psychiatrists and psychiatric beds, expansion of home care services, and use of Internet-based technologies and the cyberspace to follow up the treatment of these patients are recommended.

Dataset Information

Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts.

Background

Methods

Results

Conclusions

Publications

Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts.

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