title: Genome-wide association study of NMDA receptor coagonists in human cerebrospinal fluid and plasma.
abstract: The N-methyl-D-aspartate receptor (NMDAR) coagonists glycine, D-serine and L-proline play crucial roles in NMDAR-dependent neurotransmission and are associated with a range of neuropsychiatric disorders. We conducted the first genome-wide association study of concentrations of these coagonists and their enantiomers in plasma and cerebrospinal fluid (CSF) of human subjects from the general population (N=414). Genetic variants at chromosome 22q11.2, located in and near PRODH (proline dehydrogenase), were associated with L-proline in plasma (β=0.29; P=6.38 × 10(-10)). The missense variant rs17279437 in the proline transporter SLC6A20 was associated with L-proline in CSF (β=0.28; P=9.68 × 10(-9)). Suggestive evidence of association was found for the D-serine plasma-CSF ratio at the D-amino-acid oxidase (DAO) gene (β=-0.28; P=9.08 × 10(-8)), whereas a variant in SRR (that encodes serine racemase and is associated with schizophrenia) constituted the most strongly associated locus for the L-serine to D-serine ratio in CSF. All these genes are highly expressed in rodent meninges and choroid plexus, anatomical regions relevant to CSF physiology. The enzymes and transporters they encode may be targeted to further construe the nature of NMDAR coagonist involvement in NMDAR gating. Furthermore, the highlighted genetic variants may be followed up in clinical populations, for example, schizophrenia and 22q11 deletion syndrome. Overall, this targeted metabolomics approach furthers the understanding of NMDAR coagonist concentration variability and sets the stage for non-targeted CSF metabolomics projects.
authors: Human Neurogenetics Unit, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.|Department of Psychiatry, ZNA Hospitals, Antwerp, Belgium.|Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors: J J
authors: JJ
authors: Luykx
authors: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors: S C
authors: SC
authors: Bakker
authors: Department of Metabolic Diseases, University Medical Center Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors: W F
authors: WF
authors: Visser
authors: Department of Metabolic Diseases, University Medical Center Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors: N
authors: N
authors: Verhoeven-Duif
authors: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors: J E
authors: JE
authors: Buizer-Voskamp
authors: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors: J M
authors: JM
authors: den Heijer
authors: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors: M P M
authors: MP
authors: Boks
authors: Computer Science Department, University of California, Los Angeles, CA, USA.
authors: J H
authors: JH
authors: Sul
authors: Computer Science Department, University of California, Los Angeles, CA, USA.|Department of Human Genetics, University of California, Los Angeles, CA, USA.
authors: E
authors: E
authors: Eskin
authors: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
authors: A P
authors: AP
authors: Ori
authors: Department of Human Genetics, University of California, Los Angeles, CA, USA.
authors: R M
authors: RM
authors: Cantor
authors: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors: J
authors: J
authors: Vorstman
authors: Department of Human Genetics, University of California, Los Angeles, CA, USA.
authors: E
authors: E
authors: Strengman
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: Department of Anesthesiology, Intensive Care and Pain Management, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors: T H
authors: TH
authors: Kappen
authors: Department of Anesthesiology, Intensive Care and Pain Management, Diakonessenhuis Hospital, Utrecht, The Netherlands.
authors: E
authors: E
authors: Pariama
authors: Department of Anesthesiology, Intensive Care & Pain Management, St Antonius Hospital, Nieuwegein, The Netherlands.
authors: E P A
authors: EP
authors: van Dongen
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 & Pain Management, St Antonius Hospital, Nieuwegein, The Netherlands.
authors: P
authors: P
authors: Bruins
authors: Department of Metabolic Diseases, University Medical Center Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.|University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors: T J
authors: TJ
authors: de Koning
authors: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
authors: R S
authors: RS
authors: Kahn
authors: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.|Department of Human Genetics, University of California, Los Angeles, CA, USA.|Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
authors: R A
authors: RA
authors: Ophoff
mesh_terms: D000293:Adolescent; D000328:Adult; D000409:Alanine / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D002853:Chromatography, Liquid; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005998:Glycine / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D011392:Proline / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D011394:Proline Oxidase / Q000235:genetics; D040641:Quantitative Trait Loci; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D012694:Serine / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D026901:Membrane Transport Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C431703:SLC6A20 protein, human; D012694:Serine; D011392:Proline; D011394:Proline Oxidase; C582834:PRODH protein, human; D000409:Alanine; D005998:Glycine