Major depression and atherosclerotic disease: Linking shared genetics to pathways in blood, brain, heart, and atherosclerotic plaques
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
The increased risk of atherosclerotic diseases (stroke, coronary artery disease [CAD]) observed in depression may stem from shared pathophysiology. We examined whether: 1) major depression (MD) and atherosclerotic traits share genetic risk, and 2) altered gene expression in various tissues linked to shared genetics has a potential causal role in depression etiology.
Methods
Data from the largest genome-wide association studies of MD (N=3,887,532) and 8 atherosclerotic traits (N=26,909-1,308,460) were used in Mendelian randomization and colocalization to detect cross-trait causal associations and genomic loci containing shared causal variants. In shared loci, summary data-based Mendelian randomization estimated the effects of gene expression on MD etiology using expression quantitative trait loci datasets from whole blood, brain and heart tissues and atherosclerotic plaques from the Athero-Express Biobank Study.
Results
MD genetic liability increased risk of any stroke (OR=1.15, p=9.47×10 −8 ), ischemic stroke (OR=1.16, p=1.52×10 −7 ), small vessel disease (OR=1.34, p=4.76×10 −5 ) and CAD (OR=1.2, 95%CIs=1.13-1.26, p=3.76×10 −22 ). Eight genomic regions harbored potentially shared causal variants, including one on chromosome 7 linking MD with any stroke, ischemic stroke and CAD. Altered expression of 16 genes in blood, 10 in brain, and 6 in heart was found causal for MD etiology. In atherosclerotic plaques, one gene was linked to MD at nominal significance only.
Conclusion
Major depression and atherosclerotic diseases share genetic risk potentially acting in depression pathophysiology through expression of genes in blood, brain and heart tissues. An involvement of atherosclerotic plaques in depression etiology was not supported. Identified pathways could guide the development of new treatments to prevent depression-heightened atherosclerotic risk.
