Causal Relationships Between Major Depressive Disorder and Coronary Artery Disease Across Diverse Populations: A Bidirectional Mendelian Randomisation Study

Sep 30, 2026

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Coronary artery disease is the leading cause of cardiovascular mortality worldwide, with especially heavy impact in low- and middle-income countries. Observational findings suggest a bidirectional link between depression and coronary artery disease, yet the genetic basis and possible ancestry differences remain unclear. This open-access bidirectional two-sample Mendelian randomisation study tests causality and direction between major depressive disorder and coronary artery disease across East Asian, European, and African populations using GWAS summary statistics, supplemented by sensitivity analyses.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Introduction

Background and objectives

Methodology

Results

Conclusions

Tropical Medicine & International Health RESEARCH ARTICLE OPEN ACCESS Causal Relationships Between Major Depressive Disorder and Coronary Artery Disease Across Diverse Populations: A Bidirectional Mendelian Randomisation Study Sarah Silva1,2 | Dorothea Nitsch1 | Segun Fatumo1,2,3 1Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK | 2The African Computational Genomics Research Group (TACG), MRC/UVRI and LSHTM, Entebbe, Uganda | 3Precision Healthcare University Research Institute, Queen Mary University of London, London, UK Correspondence: Segun Fatumo ([s.fatumo@qmul.ac.uk](s.fatumo@qmul.ac.uk)) Received: 13 May 2025 | Accepted: 2 October 2025 Funding: This research was entirely self-funded. Keywords: bidirectional two-sample Mendelian randomisation analysis | coronary artery disease | coronary heart disease | depression | major depressive disorder | Mendelian randomisation | multi-ancestry ABSTRACT Background and Objectives: Coronary artery disease remains the leading cause of cardiovascular mortality worldwide, with a disproportionate burden in low-and middle-income countries. Although observational studies have established a bidirectional relationship between depression and coronary artery disease, the underlying genetic basis of this association remains unclear, particularly in underrepresented diverse-ancestry populations. Establishing whether this relationship is causal and whether it differs by ancestry is critical for informing targeted and equitable prevention strategies. Methodology: This study employed a bidirectional two-sample Mendelian randomisation framework to investigate the causal relationship between major depressive disorder and coronary artery disease across East Asian, European and African populations. Using summary statistics from large-scale genome-wide association studies, we assessed both the direction and strength of genetic associations between major depressive disorder and coronary artery disease. Sensitivity analyses were conducted to test the robustness of the findings. Results: Genetically predicted major depressive disorder was associated with increased coronary artery disease risk in European populations, confirming a causal effect consistent with prior evidence. In East Asians, we found a potentially false-positive result suggesting an inverse association between genetic liability to coronary artery disease and major depressive disorder (IVWOR = 0.942; p = 0.040), which was not supported across Mendelian randomisation sensitivity analyses and did not hold true after Bonferroni correction. In African ancestry populations, no significant causal effects were detected in either direction, due to wide confidence intervals resulting from limited sample sizes. Conclusions: Our findings provide evidence for a causal relationship between depression and coronary artery disease in Europeans and suggest potential ancestry-specific variation in this relationship, with a novel inverse association between coronary artery disease and major depressive disorder observed in East Asians requiring further replication and validation. These results highlight how limited data availability in underrepresented populations constrains causal inference, underscoring the need for more inclusive genetic research to inform equitable, population-relevant public health strategies. | Sustainable Development Goal: Reduced Inequalities; Good Health and Wellbeing; Partnerships for the Goals | | --- | | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
© 2025 The Author(s) . Tropical Medicine & International Health published by John Wiley & Sons Ltd. | 80 Tropical Medicine & International Health, 2026; 31:80–90 [https://doi.org/10.1111/tmi.70051](https://doi.org/10.1111/tmi.70051) 1

FAQs

What question does the study aim to answer about depression and coronary artery disease?

It evaluates whether the relationship between major depressive disorder and coronary artery disease is causal, and whether it varies across ancestries.

How was causality tested in this research?

The study used a bidirectional two-sample Mendelian randomisation framework with GWAS summary statistics to assess both direction and strength of genetic associations, along with sensitivity analyses.

What were the main findings in different ancestry groups?

In European populations, genetically predicted major depressive disorder increased coronary artery disease risk, supporting a causal effect. In East Asians, a potentially false-positive inverse signal appeared but was not confirmed by sensitivity checks and did not survive Bonferroni correction; in African ancestry populations, no significant effects were detected due to wide confidence intervals.

Sep 30, 2026

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