Polygenic loading for major depression is associated with specific medical comorbidity

Abstract

Major depressive disorder frequently co-occurs with medical disorders, raising the possibility of shared genetic liability. Recent identification of 15 novel genetic loci associated with depression allows direct investigation of this question. In cohorts of individuals participating in biobanks at two academic medical centers, we calculated polygenic loading for risk loci reported to be associated with depression. We then examined the association between such loading and 50 groups of clinical diagnoses, or topics, drawn from these patients' electronic health records, determined using a novel application of latent Dirichilet allocation. Three topics showed experiment-wide association with the depression liability score; these included diagnostic groups representing greater prevalence of mood and anxiety disorders, greater prevalence of cardiac ischemia, and a decreased prevalence of heart failure. The latter two associations persisted even among individuals with no mood disorder diagnosis. This application of a novel method for grouping related diagnoses in biobanks indicate shared genetic risk for depression and cardiac disease, with a pattern suggesting greater ischemic risk and diminished heart failure risk.

Figure 1

Illustration of the process of topic modeling as applied in this study.

Figure 2

Distribution of associations of polygenic risk scores (PRS) by topic (x axis) and minimum P-value across seven PRS tranches (yaxis).

Figure 3

Heat map of association for all topics, by polygenic risk scores (PRS) tranche excluding depression cases.