Dissecting pleiotropy between major depressive disorder and physical disease comorbidities

Woodward, DJ; Reay, WR; Wormington, B; Diaz-Torres, S; Ong, JS; Gerring, ZF; Thorp, JG; Derks, EM

Author(s): Woodward, DJ; Reay, WR; Wormington, B; Diaz-Torres, S; Ong, JS; Gerring, ZF; Thorp, JG; Derks, EM;
Details: Publication Year 2026-09,Volume 58,Issue #9,Page 2201-2210
Journal Title: Nature Genetics
Abstract: Major depressive disorder (MDD) is characterized 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. Here, to this end, we mapped patterns of pleiotropy by defining four clusters of physical diseases (cardiovascular, metabolic, gastrointestinal and immune) and analyzed their genetic relationships with MDD using genomic structural equation modeling. 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 (beta = 0.63, s.e. = 0.05, P = 3.04 x 10(-30)). In addition, we identified independent loci associated with the shared genetic liability between each disease cluster and MDD, revealing different pleiotropic components. Characterization of these loci revealed previously unidentified associations with MDD and physical disease traits, along with unique biological pathways, drug groups, cell types and genes associated with 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.
Publisher: Springer Nature
Keywords: *Major Depressive Disorder/genetics/epidemiology; Humans; *Genetic Pleiotropy/genetics; Comorbidity; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide/genetics; Genome-Wide Association Study; Gastrointestinal Diseases/genetics/epidemiology; Cardiovascular Diseases/genetics/epidemiology; Metabolic Diseases/genetics/epidemiology; Immune System Diseases/genetics/epidemiology
Research Division(s): Genetics and Gene Regulation
PubMed ID: 42649390
Publisher's Version: https://doi.org/10.1038/s41588-026-02735-3
Open Access at Publisher's Site: https://doi.org/10.1038/s41588-026-02735-3
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-09-07 09:09:49

Last Modified: 2026-09-14 09:09:13