Abstract 10480: Depression and Coronary Artery Disease Share Genetic Risk Factors Enriched in Inflammation and Cardiomyopathy-Associated Pathways

• Published in: Circulation (New York, N.Y.) Vol. 146; no. Suppl_1; p. A10480
• Main Authors: Singh, Kritika, Miller-Fleming, Tyne W, Lee, Hyunjoon, Sealock, Julia M, Gustavson, Daniel E, Smoller, Jordan W, Davis, Lea
• Format: Journal Article
• Language: English
• Published: Lippincott Williams & Wilkins 08.11.2022
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.146.suppl_1.10480

Coronary artery disease (CAD) and depression are highly prevalent (7% and 8% respectively), comorbid diseases. Approximately 40% of adults who are initially diagnosed with either CAD or depression will also develop the other condition. We have observed that the polygenic risk scores for depression were significantly associated with CAD in a large hospital population even in patients without any psychiatric diagnoses and after adjusting for known CAD risk factors. This suggests that some proportion of genes that increase susceptibility to depression act pleiotropically to increase CAD risk. To identify the genes increasing risk for both CAD and depression we performed a cross-tissue S-MultiXcan analysis on the summary statistics for CAD (CARDIoGRAMplusC4D Consortium) and depression (PGC and UK Biobank). We identified 185 genes associated with both depression and CAD, representing a three-fold enrichment of shared associations (P value <1.718e-43). Next we performed a pathway enrichment analysis and observed that these genes were enriched for inflammation and cardiomyopathy-associated pathways. We then used electronic health records at Vanderbilt, to test the prevalence of cardiomyopathy in patients with comorbid depression and CAD. We found that the depression-CAD cohort had a significantly increased prevalence of cardiomyopathy diagnoses ( OR = 1.27, 95%C.I. = 1.17-1.30, P value = 3.69 e-9) compared to patients with CAD after we controlled for Type 2 Diabetes, hypertension, smoking and median BMI. We replicated these findings across two external cohorts - All of Us and Massachusetts General Hospital health records. Using a Genomic structural equation model (GSEM), we observed that inflammatory markers white blood cell (WBC) count and platelet count explained 1% and 16% of the SNP-based genetic correlation between depression and CAD, respectively in a single factor. The mediation paths models using the summary statistics data show that WBC and platelets mediate approximately 1% and 13% of comorbidity and together explain 14.4% of the total genetic correlation between depression-CAD. These results highlight cardiomyopathy and inflammation as an important biological link in the comorbid manifestation of CAD and depression.