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Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid

Molecular Psychiatry volume 19, pages 228–234 (2014)Cite this article

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Abstract

Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype–phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized β=0.32, P=4.92 × 10−8), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (β=0.21; Punadjusted=5.6 × 10−7; Pcorrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.

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Authors and Affiliations

  1. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands

    J J Luykx, S C Bakker, M Neeleman, L Mentink, J E Buizer-Voskamp, R S Kahn & R A Ophoff

  2. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    J J Luykx, E Strengman, L Mentink, K van Eijk & J van Setten

  3. Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

    E Lentjes

  4. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA

    J DeYoung, S de Jong & R A Ophoff

  5. Computer Science Department, University of California, Los Angeles, Los Angeles, CA, USA

    J H Sul & E Eskin

  6. Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA

    E Eskin, R M Cantor, A Lu & R A Ophoff

  7. Department of Anesthesiology, Ter Gooi Hospitals, Hilversum, The Netherlands

    M van Amerongen

  8. Department of Anesthesiology, Intensive Care and Pain Management, St Antonius Hospital, Nieuwegein, The Netherlands

    E P A van Dongen & P Bruins

  9. Department of Anesthesiology, Central Military Hospital, Utrecht, The Netherlands

    P Keijzers

  10. Department of Anesthesiology, Intensive Care and Pain Management, University Medical Center Utrecht, Utrecht, The Netherlands

    T Kappen

  11. Department of Anesthesiology, Intensive Care and Pain Management, Diakonessenhuis Hospital, Utrecht, The Netherlands

    P Borgdorff

  12. Department of Psychiatry, Academic Medical Center, Amsterdam, The Netherlands

    E M Derks

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  1. J J Luykx
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  2. S C Bakker
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Correspondence to R A Ophoff.

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Additional information

The following URLs were used for statistical analyses, to generate plots and as information resources:

http://csg.sph.umich.edu/locuszoom/ http://genome.ucsc.edu/ http://www.ncbi.nlm.nih.gov/pubmed/ http://www.r-project.org http://www.broadinstitute.org/mammals/haploreg

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Luykx, J., Bakker, S., Lentjes, E. et al. Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid. Mol Psychiatry 19, 228–234 (2014). https://doi.org/10.1038/mp.2012.183

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