title: Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid.
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; P unadjusted=5.6 × 10(-7); P corrected=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.
authors: 1] Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands [2] Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: J J
authors: JJ
authors: Luykx
authors: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: S C
authors: SC
authors: Bakker
authors: Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: E
authors: E
authors: Lentjes
authors: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: M
authors: M
authors: Neeleman
authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: E
authors: E
authors: Strengman
authors: 1] Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands [2] Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: L
authors: L
authors: Mentink
authors: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
authors: J
authors: J
authors: DeYoung
authors: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
authors: S
authors: S
authors: de Jong
authors: Computer Science Department, University of California, Los Angeles, Los Angeles, CA, USA.
authors: J H
authors: JH
authors: Sul
authors: 1] Computer Science Department, University of California, Los Angeles, Los Angeles, CA, USA [2] Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
authors: E
authors: E
authors: Eskin
authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: K
authors: K
authors: van Eijk
authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: J
authors: J
authors: van Setten
authors: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: J E
authors: JE
authors: Buizer-Voskamp
authors: Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
authors: R M
authors: RM
authors: Cantor
authors: Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
authors: A
authors: A
authors: Lu
authors: Department of Anesthesiology, Ter Gooi Hospitals, Hilversum, The Netherlands.
authors: M
authors: M
authors: van Amerongen
authors: Department of Anesthesiology, Intensive Care and Pain Management, St Antonius Hospital, Nieuwegein, The Netherlands.
authors: E P A
authors: EP
authors: van Dongen
authors: Department of Anesthesiology, Central Military Hospital, Utrecht, The Netherlands.
authors: P
authors: P
authors: Keijzers
authors: Department of Anesthesiology, Intensive Care and Pain Management, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: T
authors: T
authors: Kappen
authors: Department of Anesthesiology, Intensive Care and Pain Management, Diakonessenhuis Hospital, Utrecht, The Netherlands.
authors: P
authors: P
authors: Borgdorff
authors: Department of Anesthesiology, Intensive Care and Pain Management, St Antonius Hospital, Nieuwegein, The Netherlands.
authors: P
authors: P
authors: Bruins
authors: Academic Medical Center, Department of Psychiatry, Amsterdam, The Netherlands.
authors: E M
authors: EM
authors: Derks
authors: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: R S
authors: RS
authors: Kahn
authors: 1] Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands [2] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA [3] Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
authors: R A
authors: RA
authors: Ophoff
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics; D000328:Adult; D015306:Biogenic Monoamines / Q000134:cerebrospinal fluid*; D002880:Chromosomes, Human, Pair 11; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid*; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid*; D016014:Linear Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D001523:Mental Disorders / Q000235:genetics; D008734:Methoxyhydroxyphenylglycol / Q000134:cerebrospinal fluid*; D020641:Polymorphism, Single Nucleotide; D025521:Tumor Suppressor Proteins
chemical_list: D015306:Biogenic Monoamines; C477880:CSMD1 protein, human; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; D008734:Methoxyhydroxyphenylglycol; D006897:Hydroxyindoleacetic Acid; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C116137:PDE9A protein, human; D006719:Homovanillic Acid