Comorbidity alters the genetic relationship between anxiety disorders and major depression

Comorbid anxiety disorders (ANX) and major depression (MD) have worse clinical outcomes than either disorder alone. Analysis of genomic data based on comorbidity status may reveal more precise biological pathways and causal relationships with potential clinical implications. We investigated the genetic relationship between ANX and MD with and without mutual comorbidity.

We leveraged data from UK Biobank to perform disorder-specific genome-wide association studies (GWAS) of ANX-only (n=189,422) and MD-only (n=194,339) and generate polygenic risk scores (PRS). The Norwegian Mother, Father, and Child Cohort (MoBa, n = 130,992) served to test the associations of PRS with diagnoses. MD and ANX GWAS, including comorbidities (MD-comorbid and ANX-comorbid), were used for comparison. Genetic correlations were compared by comorbidity status, and Mendelian randomization was employed to assess causal relationships.

The MD-only PRS showed a stronger association with MD-only compared to ANX-only cases (Z=3.74; P_adjusted=0.002); however, MD-comorbid PRS did not show a significant difference (Z=2.71; P_adjusted=0.08). The genetic correlation between ANX-only and MD-only was 0.53, lower than between ANX-comorbid and MD-comorbid (0.90). ANX-only showed a causal relationship with MD-only (P_adjusted=0.015), but not vice versa, and contrasted the bidirectional causal relationship (P_adjusted=2.9e-12, and P_adjusted=9.3e-06) when comorbidity was included. Gene sets of MD-comorbid, ANX-comorbid, and MD-only, but not of ANX-only, were enriched for immune regulation pathways such as interleukin production.

ANX and MD show more distinct genetics when comorbid cases are excluded, and ANX may be causal for MD. Disorder-specific genetic studies help uncover more relevant biological mechanisms and guide tailored clinical interventions.