Comorbidity Alters the Genetic Relationship Between Anxiety Disorders and Major Depression

Area of Science:

• Psychiatric Genetics
• Genomic Epidemiology

Background:

• Anxiety disorders (ANX) and major depression (MD) exhibit significant genetic overlap, potentially due to the inclusion of comorbid cases in genome-wide association studies (GWAS).
• Investigating the genetic relationship between ANX and MD, considering comorbidity, is essential for understanding their distinct and shared genetic architectures.

Purpose of the Study:

• To investigate the genetic relationship between anxiety disorders and major depression, differentiating between disorder-only and comorbid presentations.
• To determine if excluding comorbid cases clarifies the genetic distinctions between ANX and MD.

Main Methods:

• Performed disorder-specific GWAS for ANX-only and MD-only using UK Biobank data.
• Derived polygenic risk scores (PRS) and tested their associations with ANX-only, MD-only, and comorbid ANX-MD in the Norwegian Mother, Father, and Child Cohort (MoBa).
• Compared genetic correlations and employed Mendelian randomization, analyzing GWAS data with and without comorbid cases.

Main Results:

• Polygenic risk scores for comorbid ANX-MD were more strongly associated with ANX-MD cases than with primary disorders.
• The genetic correlation between ANX-only and MD-only (rg=0.53) was substantially lower than between ANX-comorbid and MD-comorbid (rg=0.91).
• Bidirectional causal effects observed in analyses including comorbidity were attenuated when comorbid states were excluded; immune regulation pathways were enriched in MD-comorbid, ANX-comorbid, and MD-only gene sets.

Conclusions:

• The genetic distinction between ANX and MD is more pronounced when comorbid cases are excluded.
• Disorder-specific genetic studies are vital for advancing precision medicine approaches in psychiatry.