The contribution of genetic risk to the comorbidity of depression and anxiety: a multi-site electronic health records study

ImportanceDepression and anxiety are common and highly comorbid, posing a clinical and public health concern because such comorbidity is associated with poorer outcomes.ObjectiveTo evaluate association of genetic risk scores with depression and anxiety diagnosis either in isolation or comorbid with each other.DesignInternational Classification of Diseases (ICD) ninth and tenth edition codes were extracted from longitudinal electronic health records (EHR) from four EHR-linked biobanks with genetic data available. Data analysis was performed between February 2021 to October 2021.SettingEHR-linked biorepository study.ParticipantsAcross the four biobanks, 140947 patients (80601 female [57.2%] including 109592 European ancestry [77.8%], 22321 African ancestry [15.8%], and 9034 Hispanic [6.4%]) were included in the study.Main outcomes and measuresPolygenic risk scores (PRS) for depression and anxiety were computed for all participants. They were assessed for diagnosis of depression and anxiety using ICD9/10 codes. The primary outcome was a four-level depression/anxiety diagnosis group variable: neither, depression-only, anxiety-only, and comorbid. Estimated effect measures include odds ratios and the proportion of variance on the liability scale explained by the PRS.Results95992 patients had neither diagnosis (68.1%), 14918 depression-only (10.6%), 12682 anxiety-only (9.0%), and 17355 comorbid (12.3%). PRS for depression and anxiety predicted their respective diagnoses within each biobank and each ancestry with the exception of anxiety-PRS not predicting anxiety in any ancestral group from one biobank. In the meta-analysis across participants of European ancestries, both PRSs for depression and anxiety were higher in each diagnosis group compared to controls. Notably, depression-PRS (OR=1.20 per SD increase in PRS; 95% CI= 1.18-1.23) and anxiety-PRS (OR=1.07; 95% CI=1.05-1.09) had the largest effect size for the comorbid group when compared to controls. The confidence interval for the depression-PRS effect did not overlap across groups demonstrating a gradient of genetic risk across the four diagnosis groups.Conclusions and RelevanceThe genetic risk of depression and anxiety make distinct contributions to the risk of comorbid depression and anxiety, supporting the hypothesis that the correlated disorders represent distinct nosological entities.Key PointsQuestionIs the genetic risk of depression and anxiety associated with comorbidity of depression and anxiety?FindingsUsing electronic health records from four academic medical centers, this study found that genetic risk of depression and anxiety are jointly associated with clinical depression and anxiety diagnoses with better prediction occurring for a diagnosis of depression.MeaningThe genetic risk of depression and anxiety make distinct contributions to comorbid depression and anxiety, which supports the hypothesis that the correlated disorders represent distinct nosological entities.