Polygenic risk for immuno-metabolic markers and specific depressive symptoms: A multi-sample network analysis study

Area of Science:

• Psychiatry and Genetics
• Immunology and Metabolism

Background:

• Approximately 25% of major depressive disorder (MDD) patients exhibit systemic inflammation.
• Previous research linked inflammatory markers to depressive symptoms, but genetic predisposition and metabolic factors like BMI were less understood.
• The directness of inflammation-symptom associations in MDD remained unclear.

Purpose of the Study:

• To investigate associations between polygenic risk scores (PRSs) for immuno-metabolic markers and depressive symptoms.
• To explore the role of genetic predisposition and BMI in inflammation-depression links.
• To determine if inflammation-symptom associations are direct using network analysis.

Main Methods:

• Examined PRSs for C-reactive protein (CRP), IL-6, IL-10, TNF-α, and BMI against seven depressive symptoms.
• Utilized data from the UK Biobank, MARS, and STAR*D studies (total N > 112,000).
• Applied network analysis (FGL estimation and unregularized model search) to assess direct associations and consistency across samples.

Main Results:

• Network analysis revealed numerous PRS-symptom associations, with higher CRP PRS linked to appetite changes and fatigue, and higher BMI PRS to appetite changes.
• Only the association between higher CRP PRS and greater appetite changes met all three consistency criteria.
• Four associations met at least two criteria, including CRP PRS with fatigue/anhedonia and TNF-α PRS with fatigue.

Conclusions:

• Genetic predisposition to inflammation and higher BMI are primarily associated with somatic symptoms of depression.
• Network analysis provides evidence for direct associations between genetic predisposition to immuno-metabolic markers and depressive symptoms.
• Findings may aid in selecting MDD patients for clinical trials of immune-modulating therapies.