Abstract
Major depressive disorder (MDD) is phenotypically associated with cardiovascular diseases (CVD). We aim to investigate mechanisms underlying relationships between MDD and CVD in the context of shared genetic variations. Polygenic overlap analysis was used to test genetic correlation and to analyze shared genetic variations between MDD and seven cardiovascular outcomes (coronary artery disease (CAD), heart failure, atrial fibrillation, stroke, systolic blood pressure, diastolic blood pressure, and pulse pressure measurement). Mendelian randomization analysis was used to uncover causal relationships between MDD and cardiovascular traits. By cross-trait meta-analysis, we identified a set of genomic loci shared between the traits of MDD and stroke. Putative causal genes for MDD and stroke were prioritized by fine-mapping of transcriptome-wide associations. Polygenic overlap analysis pointed toward substantial genetic variation overlap between MDD and CVD. Mendelian randomization analysis indicated that genetic liability to MDD has a causal effect on CAD and stroke. Comparison of genome-wide genes shared by MDD and CVD suggests 20q12 as a pleiotropic region conferring risk for both MDD and CVD. Cross-trait meta-analyses and fine-mapping of transcriptome-wide association signals identified novel risk genes for MDD and stroke, including RPL31P12, BORSC7, PNPT11, and PGF. Many genetic variations associated with MDD and CVD outcomes are shared, thus, pointing that genetic liability to MDD may also confer risk for stroke and CAD. Presented results shed light on mechanistic connections between MDD and CVD phenotypes.
Highlights
Mental disorders and cardiovascular diseases (CVD) account for a large proportion of the total disability and morbidity worldwide [1, 2]
Participants from these datasets were either of European origins or mainly of European origins
Genetic correlation analyses indicated that Major depressive disorder (MDD) has a significant genetic correlation with coronary artery disease (CAD), heart failure, atrial fibrillation, and pulse pressure (Table 2)
Summary
Mental disorders and cardiovascular diseases (CVD) account for a large proportion of the total disability and morbidity worldwide [1, 2]. MDD is the most prevalent mental disorder and is accompanied by considerable morbidity, mortality, and a high. Depression and Cardiovascular Diseases risk of suicide [3]. Major forms of CVD include hypertension, coronary heart disease, heart failure, stroke, and atrial fibrillation. Among patients with CVD, depression is a major contributor to increased healthcare cost, mortality, and reduced quality of life [6, 7], and is considered an independent risk factor for major adverse cardiovascular events [8]. In coronary heart disease patients, the prevalence of depression is reported at 15–23% [9]
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