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

Molecular Psychiatry volume 15, pages 736–747 (2010)Cite this article

An Erratum to this article was published on 22 October 2010

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.

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Acknowledgements

We thank S Damast, S Sauer, G Ernst-Jansen, G Gajewsky and J Huber for their excellent technical assistance. This work was funded by the Max-Planck Society and the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN), Förderkennzeichen 01GS0481. The authors are responsible for the contents of this publication.

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  1. Max Planck Institute of Psychiatry, Munich, Germany

    S Kloiber, M A Kohli, T Brueckl, S Ripke, M Ising, M Uhr, A Menke, P G Unschuld, S Horstmann, D Salyakina, B Muller-Myhsok, E B Binder, F Holsboer & S Lucae

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Parts of the data have been presented in a poster presentation at the World Congress on Psychiatric Genetics, October 2007, New York, NY, USA and the Second Meeting of West European Societies of Biological Psychiatry, December 2007, Strasbourg, France.

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Kloiber, S., Kohli, M., Brueckl, T. et al. Variations in tryptophan hydroxylase 2 linked to decreased serotonergic activity are associated with elevated risk for metabolic syndrome in depression. Mol Psychiatry 15, 736–747 (2010). https://doi.org/10.1038/mp.2008.142

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