2026 ECNP Congress
PS04-4136Anhedonia, but not depressed mood, shows genetic overlap with inflammatory and metabolic disorders
Background
Inflammatory and immunological pathways have long been implicated in the pathophysiology of depression, yet the extent to which shared genetic architecture underlies these associations remains unclear. Dissecting genetic correlations between somatic inflammatory or autoimmune conditions and specific depressive subtypes and symptoms may help clarify biological pathways and improve phenotypic precision in psychiatric research. In particular, anhedonia and depressed mood, while often co-occurring, may represent genetically distinct components of depression, differing in their neurobiological underpinnings, clinical trajectories, and treatment response, with also differential links to systemic disease. The aim of the present study was to investigate the genetic association between inflammatory / autoimmune disorders and depressed mood or anhedonia using a genetic correlation approach.
Methods
We used LDAK to estimate genetic correlations (rg) between five disease GWAS datasets (for asthma bronchiale, metabolic syndrome, autoimmune thyroid disease, systemic lupus erythematosus, and atrophic gastritis) and two depression-related UK Biobank phenotypes. Anhedonia was defined as “Frequency of unenthusiasm or disinterest in the last two weeks” (n=1,653 cases against n= 331,193 controls), and depressed mood as “Frequency of depressed mood in the last two weeks” (n=3,709 cases against n=328,481 controls). The two case sets were kept separate: anyone positive for one symptom was treated as a control for the other. Heritability and coheritability estimates were also calculated, and standard errors were obtained via jackknife resampling. Bonferroni correction was applied for multiple testing across ten trait pairs.
Results
Across the ten trait pairs tested, only metabolic syndrome and anhedonia reached nominal significance (rg=0.27, SE=0.13, p=0.04). Anhedonia consistently showed positive correlations with all four interpretable disease traits, ranging from 0.19 to 0.27, including asthma (rg=0.19, SE=0.16), autoimmune thyroid disease (rg=0.20, SE=0.29), and systemic lupus erythematosus (rg=0.27, SE=0.21). The atrophic gastritis estimate with anhedonia (rg=1.14) lay outside the biologically possible range and was excluded as unreliable. Depressed mood, by contrast, gave weaker estimates with mixed signs, with correlations ranging from negative (systemic lupus erythematosus: rg=−0.13, SE=0.13) to modestly positive (atrophic gastritis: rg=0.22, SE=0.49). Notably, metabolic syndrome showed minimal genetic overlap with depressed mood (rg=0.03, SE=0.07). No pair survived Bonferroni correction.
Conclusions
Our findings suggest that anhedonia may capture a more biologically relevant dimension of depression in relation to inflammatory and autoimmune processes than depressed mood. The consistent directionality of genetic correlations between anhedonia and multiple somatic conditions, despite limited statistical power, supports the hypothesis of shared polygenic influences. The nominal association with metabolic syndrome is particularly notable given its established links to systemic inflammation and metabolic dysregulation. These results highlight the importance of symptom-level phenotyping in psychiatric genetics and suggest that aggregating heterogeneous depressive symptoms may obscure meaningful biological signals. Future studies with larger sample sizes and more refined phenotypes are needed to confirm these associations and to explore underlying mechanisms. Replication of the metabolic syndrome finding may provide further insight into shared pathways between metabolic and affective disorders, with potential implications for stratified treatment approaches.
Funding: NAP2022-I-4/2022, K143391, 2019-2.1.7-ERA-NET-2020-00005, TKP2021-EGA-25.
References
No references