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

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.

Fig. 1

Results from large-scale genome-wide association studies (GWAS) of major depressive disorder (MDD) [11], loneliness [10], and coronary artery disease (CAD) [12] can be used in disentangle relationships between the three traits. a Genome-wide genetic correlations show that all three traits share some genetic risk factors. b Mendelian randomization experiments using the top associations from GWAS as genetic instruments found no causal effect of CAD on MDD on loneliness, while the reverse tests were likely under-powered. c This study used polygenic scores for MDD and loneliness in electronic health records linked to DNA samples and found pleiotropic relationships between MDD, loneliness, and CAD even after accounting for comorbidities and conventional heart disease risk factors

Fig. 2

Results from phenome-wide association studies of polygenic scores for MDD (a) and loneliness (b) in BioVU. The red line denotes the Bonferroni threshold for statistical significance (0.05/882 = 5.67 × 10⁻⁵), and phenome-wide significant phecodes are labeled. Upward triangles indicate increased odds for a given phecode per 1-SD increased risk in the polygenic score, while downward triangles indicate reduced odds of a given phecode. Interactive plots can be viewed at: https://sealockj.shinyapps.io/mdd_loneliness_cad_interactive/

Fig. 3

Odds of CAD by decile of the polygenic score for MDD (a) and loneliness (b) in BioVU. The referent group in all calculations is the lowest polygenic score decile

Fig. 4

Risk of CAD predicted by polygenic scores for MDD (a), loneliness (b), MDD|loneliness (c), and loneliness|MDD (d) before and after adjustment for conventional heart disease risk factors. Minimally adjusted (“Minimal”) models included sex (except sex-stratified results), age, the first ten principal components of ancestry, and genotype batch. Fully adjusted (“Full”) models included additional covariates for BMI, hypertension, smoking, type 2 diabetes, blood measurements of HDL, LDL, and triglycerides, highest level of education, a polygenic score for CAD, and depressive symptoms. Values for smoking and highest level of education were unknown for ~50% of patients. These unknown values were retained in the “Full” model by modeling an explicit category for “missing” values, and were removed from the “Full - no UNK” model. Patients were excluded from the fully adjusted models if there were missing values for any of the other included covariates. The asterisk in b denotes sex × polygenic score interaction P < .05