Shared genetic architecture of anhedonia and insulin resistance–related traits

Background

Anhedonia is an impactful symptom in psychiatry that is defined as a diminished capacity to experience pleasure. It is a transdiagnostic symptom observed across multiple psychiatric disorders, including for example major depressive disorder and schizophrenia. Converging epidemiological and clinical evidence suggests that anhedonia is also associated with metabolic disturbances, particularly those related to insulin resistance, such as obesity and type 2 diabetes. These associations, however, are only partially explained by lifestyle and other health-related characteristics and the biological mechanisms underlying this co-occurrence remain poorly understood. One possibility is that shared genetic factors contribute to both anhedonia and metabolic dysregulation. This study aimed to investigate this potential genetic overlap between anhedonia and traits related to insulin resistance.

Methods

We utilized genome-wide association study (GWAS) summary statistics from large-scale consortia for anhedonia (N = 375,000) and metabolic traits, including obesity, type 2 diabetes (T2D), metabolic syndrome, body mass index (BMI), fasting glucose, fasting insulin, 2-hour glucose (2hGlu), and glycated hemoglobin (HbA1c) (N range = 63,000–934,000). Linkage disequilibrium score regression (LDSC) was applied to estimate the genetic correlations between anhedonia and each metabolic trait. To further characterize the shared genetic structure across traits, we are currently implementing genomic structural equation modelling (genomic SEM) to identify latent factors that capture the common genetic variance underlying anhedonia and insulin resistance–related traits. This approach will allow us to assess whether a higher-order genetic factor explains the observed correlations and to quantify the contribution of individual traits to this shared liability.

Results

LDSC analyses revealed significant positive genetic correlations between anhedonia and multiple insulin resistance–related traits. The strongest correlations were observed with obesity, T2D, metabolic syndrome, and BMI (rg range: 0.26–0.33, all p < 2.5e-10), indicating a modest but consistent degree of shared genetic liability. Anhedonia was also significantly correlated with fasting glucose (rg = 0.11, p=0.004) and fasting insulin (rg = 0.33, p = 3.4e-06), these associations, however, did not survive multiple testing corrections. Results with 2hGlu and HbA1c did not reach statistical significance after correction for multiple testing. These findings suggest that the genetic overlap between anhedonia and metabolic dysfunction is not limited to a single phenotype but may reflect a broader, shared biological dimension.

Conclusions

Our findings provide evidence for a shared genetic basis between anhedonia and multiple insulin resistance–related traits, supporting the hypothesis that common biological pathways contribute to both reward-related psychopathology and metabolic dysregulation. Subsequent analyses using genomic SEM will enable us to further disentangle this shared architecture and investigate the existence of latent genetic factor(s) that may underlie both domains. As anhedonia is a transdiagnostic symptom in psychiatry, learning more about the biological basis could provide a starting point for more tailored intervention strategied. Understanding the shared mechanisms could have important implications for the development of integrated prevention and treatment strategies targeting both mental and metabolic health.

References

No references