Comorbidity alters the genetic relationship between anxiety disorders and major depression
Authors: Tesfaye Markos , Shadrin Alexey , Parker Nadine , Jaholkowski Piotr , Parekh Pravesh , Kutrolli Gleda , Birkenæs Viktoria , Bakken Nora R. , Ask Helga , Frei Oleksandr , Djurovic Srdjan , Dale Anders M. , Smeland Olav B. , O’Connell Kevin S. , Andreassen Ole A. 
Published: November 2024

AbstractImportanceThere is extensive comorbidity between anxiety disorders (ANX) and major depression (MD). Most studies on the genetics of ANX do not exclude comorbid cases of MD, andvice versa,therefore confounding genetic association analyses. Disorder-specific analysis of genomic data may reveal more precise biological pathways and causal relationships.ObjectiveTo investigate the genetic relationship between disorder-specific ANX and MD compared to samples with comorbidity, including their causal relationship.Design, Setting, and ParticipantsData from UK Biobank was used to perform genome-wide association studies (GWAS) of ANX-only and MD-only, and generate disorder-specific polygenic risk scores (PRS). The Norwegian Mother, Father, and Child Cohort (MoBa) was used to test the associations of PRS with diagnosis and symptoms. MD and ANX GWAS data including comorbidities (MD-co and ANX-co) were used as comparators. Genetic correlation was assessed using LDSC, and Mendelian randomization was employed to infer causal relationships.Main Outcomes and MeasuresGWAS of ICD-10 diagnoses of ANX, MD, or both. Genetic correlations between pairs of ANX and MD phenotypes. PRS associations with diagnoses of ANX, MD, and their comorbid states, and anxiety or depressive symptoms.ResultsThe GWAS of ANX-only (9,980 cases and 179,442 controls) and MD-only (15,301 cases and 179,038 controls) showed a lower genetic correlation (0.53) than the one between ANX-co and MD-co (0.90). ANX-only showed a causal relationship with MD-only (PFDR=1.5e-02), but notvice versa, while comorbid cases showed a significant bidirectional causal relationship (PFDR=2.9e-12, PFDR=9.3e-06). The PRS-MD-only were differentially associated with MD-only compared to ANX-only cases (β= -0.08; 95%CI: -0.11, -0.03); however, this differential association was not observed for the PRS-MD-co. A similar pattern of differential association with anxiety and depressive symptoms was observed for PRS-ANX-only, but not for PRS-MD-co.Conclusions and RelevanceThe genetics and underlying biology of ANX and MD are more distinct when comorbid cases are excluded from analyses and reveals that ANX may be causal for MD. This confounding of genetic relationships as a result of comorbidity is likely to apply to other psychiatric disorders. Disorder-specific genetic studies may help uncover more relevant biological mechanisms and guide more targeted clinical interventions.Key PointsQuestionIs the high genetic correlation between anxiety disorders (ANX) and major depression (MD) due to phenotypic overlap (comorbidity) and will disorder-specific (non-comorbid) analysis provide insight into their underlying causal factors?FindingsApplying statistical genetics tools in two large population samples (UK Biobank, n=500,000; and MoBa, n= 130,000), we found a smaller genetic correlation between MD and ANX when comorbid cases were excluded. Additionally, after excluding comorbid cases, Mendelian randomization revealed that genetic liability to ANX is causally linked to MD but notvice versa.MeaningThe genetic overlap between ANX and MD may be driven by phenotypic comorbidity, which inflates their genetic correlation. The results support that ANX has a causal link to MD, suggesting that early interventions for ANX may prevent subsequent development of MD. Further, investigating the genetic underpinnings of ANX and MD, while excluding their comorbid states, may help advance precision medicine and uncover novel biological mechanisms.