Dataset Information

Mendelian randomization studies of depression: evidence, opportunities, and challenges.

ABSTRACT:

Background

Major depressive disorder (MDD) poses a significant social and economic burden worldwide. Identifying exposures, risk factors, and biological mechanisms that are causally connected to MDD can help build a scientific basis for disease prevention and development of novel therapeutic approaches.

Methods

In this systematic review, we assessed the evidence for causal relationships between putative causal risk factors and MDD from Mendelian randomization (MR) studies, following PRISMA. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions.

Results

We included methodological details and results from 52 articles. A causal link between lifestyle, metabolic, inflammatory biomarkers, particular pathological states and MDD is supported by MR investigations, although results for each category varied substantially.

Conclusions

While this review shows how MR can offer useful information for examining prospective treatment targets and better understanding the pathophysiology of MDD, some methodological flaws in the existing literature limit reliability of results and probably underlie their heterogeneity. We highlight perspectives and recommendations for future works on MR in psychiatry.

SUBMITTER: Ma WR

PROVIDER: S-EPMC10666459 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

Mendelian randomization studies of depression: evidence, opportunities, and challenges.

Ma Wang-Ran WR Zhang Lei-Lei LL Ma Jing-Ying JY Yu Fang F Hou Ya-Qing YQ Feng Xiang-Rui XR Yang Lin L

Annals of general psychiatry 20231123 1

<h4>Background</h4>Major depressive disorder (MDD) poses a significant social and economic burden worldwide. Identifying exposures, risk factors, and biological mechanisms that are causally connected to MDD can help build a scientific basis for disease prevention and development of novel therapeutic approaches.<h4>Methods</h4>In this systematic review, we assessed the evidence for causal relationships between putative causal risk factors and MDD from Mendelian randomization (MR) studies, followi ...[more]

PMID: 37996851

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Project description:BackgroundKetone bodies (KBs) are an alternative energy supply for brain functions when glucose is limited. The most abundant ketone metabolite, 3-β-hydroxybutyrate (BOHBUT), has been suggested to prevent or delay cognitive impairment, but the evidence remains unclear. We triangulated observational and Mendelian randomization (MR) studies to investigate the association and causation between KBs and cognitive function.MethodsIn observational analyses of 5506 participants aged ≥ 45 years from the Whitehall II study, we used multiple linear regression to investigate the associations between categorized KBs and cognitive function scores. Two-sample MR was carried out using summary statistics from an in-house KBs meta-analysis between the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium and Kettunen et al. (N = 45,031), and publicly available summary statistics of cognitive performance and Alzheimer's disease (AD) from the Social Science Genetic Association Consortium (N = 257,841), and the International Genomics of Alzheimer's Project (N = 54,162), respectively. Both strong (P < 5 × 10-8) and suggestive (P < 1 × 10-5) sets of instrumental variables for BOHBUT were applied. Finally, we performed cis-MR on OXCT1, a well-known gene for KB catabolism.ResultsBOHBUT was positively associated with general cognitive function (β = 0.26, P = 9.74 × 10-3). In MR analyses, we observed a protective effect of BOHBUT on cognitive performance (inverse variance weighted: βIVW = 7.89 × 10-2, PIVW = 1.03 × 10-2; weighted median: βW-Median = 8.65 × 10-2, PW-Median = 9.60 × 10-3) and a protective effect on AD (βIVW = - 0.31, odds ratio: OR = 0.74, PIVW = 3.06 × 10-2). Cis-MR showed little evidence of therapeutic modulation of OXCT1 on cognitive impairment.ConclusionsTriangulation of evidence suggests that BOHBUT has a beneficial effect on cognitive performance. Our findings raise the hypothesis that increased BOHBUT may improve general cognitive functions, delaying cognitive impairment and reducing the risk of AD.

Dataset Information

Mendelian randomization studies of depression: evidence, opportunities, and challenges.

Background

Methods

Results

Conclusions

Publications

Mendelian randomization studies of depression: evidence, opportunities, and challenges.

Similar Datasets

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