Association between serotonin 5-HT-2C receptor gene (HTR2C) polymorphisms and obesity- and mental health-related phenotypes in a large population-based cohort

Objective: Studies have shown that common single-nucleotide polymorphisms (SNPs) in the serotonin 5-HT-2C receptor (HTR2C) are associated with antipsychotic agent-induced weight gain and the development of behavioural and psychological symptoms. We aimed to analyse whether variation in the HTR2C is associated with obesity- and mental health-related phenotypes in a large population-based cohort. Method: Six tagSNPs, which capture all common genetic variation in the HTR2C gene, were genotyped in 4978 men and women from the European Prospective Investigation into Cancer (EPIC)–Norfolk study, an ongoing prospective population-based cohort study in the United Kingdom. To confirm borderline significant associations, the −759C/T SNP (rs3813929) was genotyped in the remaining 16 003 individuals from the EPIC–Norfolk study. We assessed social and psychological circumstances using the Health and Life Experiences Questionnaire. Genmod models were used to test associations between the SNPs and the outcomes. Logistic regression was performed to test for association of SNPs with obesity- and mental health- related phenotypes. Results: Of the six HTR2C SNPs, only the T allele of the –759C/T SNP showed borderline significant associations with higher body mass index (BMI) (0.23 kg m–2; (95% confidence interval (CI): 0.01–0.44); P=0.051) and increased risk of lifetime major depressive disorder (MDD) (Odds ratio (OR): 1.13 (95% CI: 1.01–1.22), P=0.02). The associations between the −759C/T and BMI and lifetime MDD were independent. As associations only achieved borderline significance, we aimed to validate our findings on the –759C/T SNP in the full EPIC–Norfolk cohort (n=20 981). Although the association with BMI remained borderline significant (β=0.20 kg m–2; 95% CI: 0.04–0.44, P=0.09), that with lifetime MDD (OR: 1.01; 95% CI: 0.94–1.09, P=0.73) was not replicated. Conclusions: Our findings suggest that common HTR2C gene variants are unlikely to have a major role in obesity- and mental health-related traits in the general population.