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Importance: Epidemiological evidence indicates that major depressive disorder (MDD) and loneliness both reduce life expectancies, but mechanisms underlying the excess morbidity are unclear. Electronic health records (EHRs) linked to genetic data offer new opportunities to address this knowledge gap. Objective: To determine the medical morbidity pattern associated with genetic risk factors for MDD and loneliness, two common psychological traits with adverse health outcomes. Design: Phenome-wide association study using EHRs spanning 1990 to 2017 from the Vanderbilt University Medical Center biobank, BioVU. Top associations with coronary artery disease (CAD) were replicated in the Atherosclerosis Risk in Communities (ARIC) cohort. Setting: Hospital-based EHR study, with replication in a population-based cohort study. Participants: 18,385 genotyped adult patients in BioVU. Replication in ARIC included 7,197 genotyped participants. All participants were of European ancestry. Exposures: Polygenic scores for MDD and loneliness were developed for each individual using previously published meta-GWAS summary statistics. Main Outcomes and Measures: The phenome-wide association study included 882 clinical diagnoses ascertained via billing codes in the EHR. ARIC included 1598 incident CAD cases. Results: BioVU patients had a median EHR length of 9.91 years. In the phenome-wide association study, polygenic scores for MDD and loneliness were significantly associated with psychiatric and cardiac phenotypes. Targeted analyses of CAD in 3,893 cases and 4,197 controls in BioVU found odds ratios of 1.11 (95% CI, 1.04-1.18; P=8.43x10-4) and 1.13 (95% CI, 1.07-1.20; P=4.51x10-6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Comparable hazard ratios in ARIC were 1.07 (95% CI, 0.99-1.14; P=0.07) and 1.07 (1.01-1.15; P=0.03). Across both studies, the increased risk persisted in women after adjusting for multiple conventional risk factors, a polygenic score for CAD, and psychiatric symptoms (available in BioVU). Controlling for genetic risk factors shared between MDD and loneliness, the polygenic score for loneliness conditioned on MDD remained associated with CAD risk, but the polygenic score for MDD conditioned on loneliness did not. Conclusions and Relevance: Genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in women. Continued research into the biological and clinical connections between the heart and mind is warranted.

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