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.

Keywords: Causality; Depression; Instrumental variables; Mendelian randomization study; Risk factors.

Fig. 1

The basic principles and core assumptions of Mendelian randomization (MR). Correlation hypothesis: IV must be strongly correlated with exposure. Independence assumption: IV must be independent of confounding factors. Exclusivity assumption: IV will only affect the outcome through exposure

Fig. 2

Cigarette smoking, excessive alcohol consumption, marijuana use, elevated circulating TG, C-reactive protein(CRP) and IL-6 levels, decreased DHA and increased omega-6: omega-3 fatty acid ratios, BMI, AAM, shorter telomere lengths, intestinal flora, type 2 diabetes mellitus, and breast cancer were associated with increased risk of major depressive disorder (MDD). In contrast, higher carbohydrate and beef intake, physical activity, higher education, early circadian preference, and living with a spouse or partner were associated with a lower risk of MDD. MR analyses have not yet established a causal relationship between genetic prediction of the prevalence of CAD, MS, types of cancer other than breast cancer, AD, JIAU, or periodontitis

Fig. 3

Flow diagram of studies included in systematic review