Genetic architecture of DCC and influence on psychological, psychiatric and cardiometabolic traits in multiple ancestry groups in UK Biobank

Background: People with severe mental illness have a higher risk of cardiometabolic disease than the general population. Traditionally attributed to sociodemographic, behavioural factors and medication effects, recent genetic studies have provided evidence of shared biological mechanisms underlying mental illness and cardiometabolic disease. We aimed to determine whether signals in the DCC locus, implicated in psychiatric and cardiometabolic traits, were shared or distinct. Methods: In UK Biobank, we systematically assessed genetic variation in the DCC locus for association with metabolic, cardiovascular and psychiatric-related traits in unrelated "white British" participants (N = 402,837). Logistic or linear regression were applied assuming an additive genetic model and adjusting for age, sex, genotyping chip and population structure. Bonferroni correction for the number of independent variants was applied. Conditional analyses (including lead variants as covariates) and trans-ancestry analyses were used to investigate linkage disequilibrium between signals. Results: Significant associations were observed between DCC variants and smoking, anhedonia, body mass index (BMI), neuroticism and mood instability. Conditional analyses and linkage disequilibrium structure suggested signals for smoking and BMI were distinct from each other and the mood traits, whilst individual mood traits were inter-related in a complex manner. Limitations: Restricting analyses in non-"white British" individuals to the phenotypes significant in the "white British" sample is not ideal, but the smaller samples sizes restricted the phenotypes possible to analyse. Conclusions: Genetic variation in the DCC locus had distinct effects on BMI, smoking and mood traits, and therefore is unlikely to contribute to shared mechanisms underpinning mental and cardiometabolic traits.