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Tryptophan hydroxylase2 gene polymorphisms predict brain serotonin synthesis in the orbitofrontal cortex in humans

Molecular Psychiatry volume 17, pages 809–817 (2012)Cite this article

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Abstract

Brain regional serotonin synthesis can be estimated in vivo using positron emission tomography (PET) and α-[(11)C]methyl-L-tryptophan (11C-AMT) trapping (K*) as a proxy. Recently, we reported evidence of lower normalized 11C-AMT trapping in the orbitofrontal cortex (OBFC) of subjects meeting the criteria for an impulsive and/or aggressive behavioral phenotype. In this study, we examined whether part of the variance in OBFC serotonin synthesis is related to polymorphisms of the gene that encodes for the indoleamine's rate-limiting enzyme in the brain, tryptophan hydroxylase-2 (TPH2). In all, 46 healthy controls had PET 11C-AMT scans and were genotyped for 11 single-nucleotide polymorphisms (SNPs) distributed across the TPH2 gene and its 5′ upstream region. Several TPH2 SNPs were associated with lower normalized blood-to-brain clearance of 11C-AMT in the OBFC. Dose–effect relationships were found for two variants (rs6582071 and rs4641527, respectively, located in the 5′ upstream region and intron 1) that have previously been associated with suicide. Associations in the OBFC remained statistically significant in a mixed larger sample of patients and controls. These results suggest that in humans, genetic factors might partly account for variations in serotonin synthesis in the OBFC.

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Acknowledgements

This study was supported by grants from FRSQ and CIHR. Dr Booij was supported by FRSQ and by a VENI award from the Netherlands Organization of Scientific Research. None of the funding organizations have a role in the design of the study, collection and data analyses.

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  1. L Booij

    Present address: 5Current address: Sainte-Justine Hospital Research Center, Montreal, QC, Canada.,

Authors and Affiliations

  1. Department of Psychiatry, McGill University, Montreal, QC, Canada

    L Booij, G Turecki, M Leyton, P Gravel & C Benkelfat

  2. McGill Group for Suicide Studies, Douglas Hospital, McGill University, Montreal, QC, Canada

    G Turecki & C Lopez De Lara

  3. McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada

    M Leyton, M Diksic & C Benkelfat

  4. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    M Leyton, M Diksic & C Benkelfat

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Booij, L., Turecki, G., Leyton, M. et al. Tryptophan hydroxylase2 gene polymorphisms predict brain serotonin synthesis in the orbitofrontal cortex in humans. Mol Psychiatry 17, 809–817 (2012). https://doi.org/10.1038/mp.2011.79

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