Dissecting the mediating and moderating effects of depression on the associations between traits and coronary artery disease: A two-step Mendelian randomization and phenome-wide interaction study

BACKGROUND: Depression is often present concurrently with coronary artery disease (CAD), a disease with which it shares many risk factors. However, the manner in which depression mediates and moderates the association between traits (including biomarkers, anthropometric indicators, lifestyle behaviors, etc.) and CAD is largely unknown. METHODS: In our causal mediation analyses using two-step Mendelian randomization (MR), univariable MR was first used to investigate the causal effects of 108 traits on liability to depression and CAD. The traits with significant causal effects on both depression and CAD, but not causally modulated by depression, were selected for the second-step analyses. Multivariable MR was used to estimate the direct effects (independent of liability to depression) of these traits on CAD, and the indirect effects (mediated via liability to depression) were calculated. To investigate the moderating effect of depression on the association between 364 traits and CAD, a cross-sectional phenome-wide interaction study (PheWIS) was conducted in a study population from UK Biobank (UKBB) (N=275,257). Additionally, if the relationship between traits and CAD was moderated by both phenotypic and genetically predicted depression at a suggestive level of significance (P(interaction)≤0.05) in the PheWIS, the results were further verified by a cohort study using Cox proportional hazards regression. RESULTS: Univariable MR indicated that 10 of 108 traits under investigation were significantly associated with both depression and CAD, which showed a similar direct effect compared to the total effect for most traits. However, the traits “drive faster than speed limit” and “past tobacco smoking” were both exceptions, with the proportions mediated by depression at 24.6% and 7.2%, respectively. In the moderation analyses, suggestive evidence of several traits was found for moderating effects of phenotypic depression or susceptibility to depression, as estimated by polygenic risk score, including chest pain when hurrying, reason of smoking quitting and weight change. Consistent results were observed in survival analyses and Cox regression. CONCLUSION: The independent role of traits in CAD pathogenesis regardless of depression was highlighted in our mediation analyses, and the moderating effects of depression observed in our study may be helpful for CAD risk stratification and optimized allocation of scarce medical resources.