Polymorphisms in tryptophan hydroxylase 2 leading to decreased serotonergic activity contribute to elevated risk for metabolic syndrome in depression

The comorbidity of major depression (MD) and the metabolic syndrome (MetS) has been well established in several studies, however the underlying processes are still unclear. Serotonergic neurotransmission has been shown to be involved in both disorders. The rate limiting enzyme for serotonin biosynthesis in the CNS tryptophan hydroxylase 2 (TPH2) is therefore a strong candidate. We investigated whether genetic variants in TPH2 may contribute to the increased prevalence of MetS in subjects with a history of MD. In a case control study of 988 MD patients and 1023 psychiatric healthy controls of Caucasian origin diagnosis of MD was ascertained with the WHO SCAN-Interview, MetS prevalence was defined according to the IDF criteria. 41 SNPs fully covering the TPH2 gene region were genotyped in stage one (n=600) resulting in significant associations of MetS in patients with MD and SNPs in TPH2 after correction for age, gender and multiple testing. We were able to confirm the significant association in stage two (n=1411). Risk-genotypes and risk-haplotypes could be linked to lower TPH2 mRNA expression and lower 5-HIAA levels previously reported in functional studies. Our findings suggest that TPH2 polymorphisms characterize a subgroup of depressed patients who are especially prone to develop metabolic disorders contributing to the MetS. We postulate that a genotype dependent impairment of serotonergic neurotransmission is involved in this gene-disease interaction.