Dataset Information

Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis.

ABSTRACT:

Background

Major depressive disorder (MDD) is common in multiple sclerosis (MS) and its incidence rises before MS diagnosis. However, the causality and direction of this association remain unclear.

Objective

The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR).

Methods

We selected genetic instruments associated with risk of MDD (n = 660,937 cases; 1,453,489 controls) and MS (n = 47,429 cases; 68,374 controls). Using two-sample MR, we examined putative causal effects in either direction, with sensitivity analyses to assess pleiotropy. Also, we adjusted for body mass index (BMI) in multivariable MR.

Results

We found no effect of genetic liability to MDD on the odds of MS (OR = 1.07/doubling in odds, 95% CI = 0.90-1.28). Similarly, our findings did not support a causal effect of genetic liability to MS on MDD (OR = 1.00/doubling in odds, 95% CI = 0.99-1.01). Despite heterogeneity, sensitivity analyses indicated that bias from pleiotropy was unlikely. Conversely, genetic predisposition toward higher BMI increased the odds of MS (OR = 1.34/SD increase, 95% CI = 1.09-1.65) and MDD (OR = 1.08, 95% CI = 1.01-1.15).

Conclusion

This study does not support a causal association between MDD genetic liability and MS susceptibility, and vice versa. Genetic evidence suggesting commonality of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis.

SUBMITTER: Harroud A

PROVIDER: S-EPMC8364919 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis.

Harroud Adil A Marrie Ruth Ann RA Fitzgerald Kathryn C KC Salter Amber A Lu Yi Y Patel Mitulkumar M Kowalec Kaarina K

Multiple sclerosis (Houndmills, Basingstoke, England) 20210216 13

<h4>Background</h4>Major depressive disorder (MDD) is common in multiple sclerosis (MS) and its incidence rises before MS diagnosis. However, the causality and direction of this association remain unclear.<h4>Objective</h4>The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR).<h4>Methods</h4>We selected genetic instruments associated with risk of MDD (<i>n</i> = 660,937 cases; 1,453,489 controls) and MS (<i>n</i> = 47,429 cases; 68,3 ...[more]

PMID: 33591230

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Project description:BackgroundObservational studies have suggested an association between multiple sclerosis (MS) and cortical structure, but the results have been inconsistent.ObjectiveWe used two-sample Mendelian randomization (MR) to assess the causal relationship between MS and cortical structure.MethodsMS data as the exposure trait, including 14,498 cases and 24,091 controls, were obtained from the International Multiple Sclerosis Genetics Consortium. Genome-wide association study (GWAS) data for cortical surface area (SAw/nw) and thickness (THw/nw) in 51,665 individuals of European ancestry were obtained from the ENIGMA Consortium. The inverse-variance weighted (IVW) method was used as the primary analysis for MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Enrichment analysis was performed on MR analyses filtered by sensitivity analysis.ResultsAfter IVW and sensitivity analysis filtering, only six surviving MR results provided suggestive evidence supporting a causal relationship between MS and cortical structure, including lingual SAw (p = .0342, beta (se) = 5.7127 (2.6969)), parahippocampal SAw (p = .0224, beta (se) = 1.5577 (0.6822)), rostral middle frontal SAw (p = .0154, beta (se) = - 9.0301 (3.7281)), cuneus THw (p = .0418, beta (se) = - 0.0020 (0.0010)), lateral orbitofrontal THw (p = .0281, beta (se) = 0.0025 (0.0010)), and lateral orbitofrontal THnw (p = .0417, beta (se) = 0.0029 (0.0014)). Enrichment analysis suggested that leukocyte cell-related pathways, JAK-STAT signaling pathway, NF-kappa B signaling pathway, cytokine-cytokine receptor interaction, and prolactin signaling pathway may be involved in the effect of MS on cortical morphology.ConclusionOur results provide evidence supporting a causal relationship between MS and cortical structure. Enrichment analysis suggests that the pathways mediating brain morphology abnormalities in MS patients are mainly related to immune and inflammation-driven pathways.

Project description:Endometriosis, identified by the abnormal growth of endometrial cells beyond the inner lining of the uterus, often manifests through symptoms like painful menstruation and challenges in conceiving. Observational studies suggest that endometriosis is often comorbid with mental disorders, including anxiety and depression. The nature of these connections, whether they are causal, is still debated and calls for further empirical evidence. We utilized a bidirectional 2-sample Mendelian randomization (MR) approach, harnessing genome-wide association study data to explore the connections among depression, anxiety, neuroticism, and endometriosis. To scrutinize the causative connections between mental health issues and endometriosis, Inverse Variance Weighting (IVW) was employed as the primary analytical tool, complemented by Weighted Median Estimation, Simple mode, Weighted mode, and MR-Egger regression for additional analysis. To examine the potential for reverse causation, reverse MR was applied. To strengthen the reliability of our findings, we carried out sensitivity analyses that included heterogeneity tests, tests for pleiotropy, and leave-one-out analyses. The IVW analysis revealed a significant correlation between the genetic inclination towards depression and a heightened risk of developing endometriosis [Odds Ratio (OR) = 1.151, 95% Confidence Interval (CI) = 1.025-1.293, P = .017]. Similarly, a genetic predisposition to neuroticism was significantly associated with an increased risk of endometriosis (OR = 1.128, 95% CI = 1.038-1.226, P = .004). However, no causative link was found between genetic susceptibility to anxiety and the occurrence of endometriosis. Reverse MR analysis did not support a bidirectional genetic susceptibility between endometriosis and psychiatric disorders. The MR analysis presents genetic data supporting the notion that depression and neuroticism are risk factors for endometriosis. Conversely, it found no evidence of a causal connection between anxiety and the development of endometriosis. Enhancing mental health treatment should be considered a preventive measure against endometriosis.

Dataset Information

Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis.

Background

Objective

Methods

Results

Conclusion

Publications

Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis.

Similar Datasets

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