Dissecting pleiotropy between major depressive disorder and physical disease comorbidities

Abstract Major Depressive Disorder (MDD) is characterised by substantial comorbidity with medical conditions. To achieve better outcomes for patients with MDD, an improved understanding of the mechanisms underlying pervasive comorbidities is required. To this end, we map patterns of pleiotropy by defining four clusters of physical diseases (cardiovascular, metabolic, gastrointestinal, and immune) to analyse their genetic relationship with MDD using genomic structural equation modelling. Three disease clusters exhibited independent associations with MDD and accounted for 47% of MDD h 2 SNP , with the gastrointestinal disease cluster having the strongest association (β = 0.63, SE = 0.05, P = 3.04 × 10 -30 ). Additionally, we identified independent loci associated with the shared genetic liability between each disease cluster and MDD, revealing different pleiotropic components. Characterisation of these loci revealed previously unidentified associations with MDD and physical disease traits, along with unique biological pathways, drug groups, cell types and genes related to each disease-MDD cluster. Our findings reveal genetic connections implicating the gut-brain axis as a key mechanism underlying the comorbidity of physical diseases in MDD. This work advances our understanding of MDD by highlighting unique and shared genetic components across different disease systems.