Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease

Pierre Fontanillas,Dorret I. Boomsma,Guanhua Chen,Rebecca T. Levinson,Quinn S. Wells,Julia Sealock,Abdel Abdellaoui,Macrae R.f. Linton ,Jessica Dennis,Péter Straub ,Eric Farber‐Eger ,Douglas M. Ruderfer ,Lea K. Davis,Sandra Sanchez‐Roige ,Abraham A. Palmer,Nancy J. Cox,Jacob Franco,Wen‐Liang Song ,Sarah L. Elson,Donald Hucks,Sarah Fong,Jonathan D. Mosley

doi:10.1038/s41380-019-0614-y

Abstract

Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04–1.18; P 8.43 × 10−4) and 1.13 (95% CI, 1.07–1.20; P 4.51 × 10−6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03–1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95–1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99–1.14; P = 0.07) and 1.07 (1.01–1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.

Highlights

Major depressive disorder (MDD) is among the most common mental disorders, with a lifetime prevalence as high as 17% [1]
The phenome-wide association study of the polygenic score for MDD identified phenome-wide significant associations with “Mood disorders”, and “Depression” (OR, 1.10 [95% CI, 1.05–1.15]; P = 1.13 × 10−5), parent codes for MDD, as expected (Fig. 2a; interactive plots available at: https://sea lockj.shinyapps.io/mdd_loneliness_cad_interactive/)
The remaining six phecodes that were significant after Bonferroni correction were related to acute and chronic heart diseases and their associated risk factors, including “Ischemic heart disease” (OR, 1.09 [95% CI, 1.05–1.14]; P = 8.28 × 10−6) and “Coronary atherosclerosis” (OR, 1.10 [95% CI, 1.05–1.14]; P = 1.08 × 10−5)

Summary

Introduction

Major depressive disorder (MDD) is among the most common mental disorders, with a lifetime prevalence as high as 17% [1]. Cardiovascular disease [2] and 30–74% of patients who have cardiac events will meet criteria for MDD (Fig. 1a) [3]. Understanding the complex relationship between these two traits is critical to reducing early mortality, as comorbid MDD is associated with a fivefold increased risk of cardiac mortality within 6 months of a myocardial infarction [3]. In addition to the frequently documented, but poorly understood, relationship between MDD and cardiac health, recent evidence strongly suggests that chronic loneliness—independent from MDD — increases the risk of heart disease and early mortality. Analyses of ~500,000 participants in the UK biobank showed that loneliness increased the risk of cardiovascular disease incidence by 50% [4] and Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary

Methods

Results

Discussion

Conclusion