Comorbidity Alters the Genetic Relationship Between Anxiety Disorders and Major Depression

Abstract Background The extensive genetic overlap between anxiety disorders (ANX) and major depression (MD) may partly reflect inclusion of comorbid cases in genome-wide association studies (GWAS). We investigated this genetic relationship between ANX and MD with and without mutual comorbidity. Methods Using UK Biobank, we performed disorder-specific GWAS for ANX-only (cases/controls = 9,980/179,442) and MD-only (cases/controls = 15,301/179,038) and derived polygenic risk scores (PRS). In the Norwegian Mother, Father, and Child Cohort (MoBa), we tested associations of PRS with MD-only (N=7,486), ANX-only (N=1,992), and comorbid (ANX-MD) (N=3,468) and controls (N=85,851). PRS associations with anxiety and depression symptoms were tested in MoBa (N=54,862). GWAS including comorbid cases (MD-comorbid or ANX-comorbid) were used for comparison. Genetic correlations were compared by comorbidity status, and Mendelian randomization was employed to assess causal relationships. Results MD-comorbid and ANX-comorbid PRS showed stronger association with ANX-MD cases than with their primary disorders, MD-only (Z=-2.82; P adjusted =0.01) and ANX-only (Z=-2.36; P adjusted =0.03), respectively. MD-only PRS was more strongly associated with MD-only than with ANX-only cases (Z=3.63; P adjusted =6.9e-04). The genetic correlation was lower between ANX-only and MD-only (rg=0.53, SE=0.11) than between ANX-comorbid and MD-comorbid (rg=0.91, SE=0.01). Bidirectional causal effects observed in comorbidity-inclusive analyses were attenuated to null when comorbid states were excluded. Gene sets of MD-comorbid, ANX-comorbid, and MD-only, but not of ANX-only, were enriched for the immune regulation pathway – interleukin-21 production. Conclusions The genetic distinction between ANX and MD becomes more pronounced when comorbid cases are excluded. The findings underscore the importance of disorder-specific genetic studies for advancing precision medicine.