Variations in tryptophan hydroxylase 2 linked to decreased serotonergic activity are associated with elevated risk for metabolic syndrome in depression

Abstract

Major depression and the metabolic syndrome (MetS) are interacting clinical conditions influenced by genetic susceptibility. For both disorders, impaired serotonergic neurotransmission in specific brain areas has been suggested. This led us to investigate whether variants in the gene coding for tryptophan hydroxylase 2 (TPH2), the brain-specific and rate-limiting enzyme for serotonin biosynthesis, might be predictive for an increased liability for the development of MetS in depressed patients. In a case-control study consisting of 988 patients with recurrent unipolar depression (RUD) and 1023 psychiatric healthy controls, MetS components were ascertained according to the International Diabetes Foundation criteria. A total of 41 single nucleotide polymorphisms fully covering the TPH2 gene region were genotyped in stage 1 (300 patients/300 controls), resulting in significant genetic associations of polymorphisms located in exon 7 and intron 8 of TPH2 and the occurrence of MetS in depressed patients after correction for age, gender and multiple testing (51 RUD-MetS/179 RUD-non-MetS). We were able to confirm the significant association of rs17110690 in stage 2 (688 patients/723 controls; 110 RUD-MetS/549 RUD-non-MetS) and to link risk-genotypes and risk-haplotypes for MetS to lower TPH2 mRNA expression and to lower 5-hydroxyindoleacetic acid levels in cerebrospinal fluid 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 induced by a genotype-dependent impairment of serotonergic neurotransmission. Identifying depressed patients at high risk for MetS using genetic variants could have direct clinical impact on individualized disease management and prevention strategies.

Association of treatment response with obesity and other metabolic risk factors in adults with depressive disorders: Results from a National Depression Cohort study in Korea (the CRESCEND study)

“…Although it is difficult to directly compare our results with previous results (Carroll et al, 2009;Kloiber et al, 2010;Richter et al, 2010;van Reedt Dortland et al, 2010) due to differences in criteria, the race/ethnicity and age of sample and prevalence of hypertension, hypercholesterolemia, and obesity in the present study were in accordance with results from previous studies of MDD patients. Only the prevalence of hyperglycemia (25.0%) was higher in the present study than in previous studies.…”

Sex- and age-specific associations between major depressive disorder and metabolic syndrome in two general population samples in Germany

“…The less active polymorphism of the tryptophan hydroxylase 2 (TPH2), the brain-specific and ratelimiting enzyme for serotonin biosynthesis, increases the risk for MetS in participants with recurrent MDD (67). This is in line with previous findings on low serotonergic function in MetS (34).…”

“…For the understanding of the shared pathophysiology of MDD and MetS, one promising genetic risk factor was recently described (67). The less active polymorphism of the tryptophan hydroxylase 2 (TPH2), the brain-specific and ratelimiting enzyme for serotonin biosynthesis, increases the risk for MetS in participants with recurrent MDD (67).…”

Depression trajectories and the association with metabolic adversities among the middle-aged adults

“…Another potential explanation is that chronic systemic inflammation, a key mechanism in MetS (Kloting and Bluher, 2014) is also associated with depression (Lopresti et al, 2014). Autonomous neurotransmitter imbalance (Hamer and Malan, 2012) and genetic factors (Kloiber et al, 2010) have also been proposed as mechanisms linking the two conditions.…”