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Genome-wide association study of NMDA receptor coagonists in human cerebrospinal fluid and plasma

Luykx, J. J. ; Bakker, S. C. ; Visser, W. F. ; Verhoeven-Duif, N. ; Buizer-Voskamp, J. E. ; Den Heijer, J. M. ; Boks, M. P.M. ; Sul, J. H. ; Eskin, E. and Ori, A. P. , et al. (2015) In Molecular Psychiatry 20(12). p.1557-1564
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Psychiatry
volume
20
issue
12
pages
8 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:84947617141
  • pmid:25666758
ISSN
1359-4184
DOI
10.1038/mp.2014.190
language
English
LU publication?
no
id
6f82c8cd-fe0e-4620-a0e8-68c9086d34ac
date added to LUP
2020-02-26 10:02:59
date last changed
2024-04-03 03:28:09
@article{6f82c8cd-fe0e-4620-a0e8-68c9086d34ac,
  abstract     = {{<p>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.</p>}},
  author       = {{Luykx, J. J. and Bakker, S. C. and Visser, W. F. and Verhoeven-Duif, N. and Buizer-Voskamp, J. E. and Den Heijer, J. M. and Boks, M. P.M. and Sul, J. H. and Eskin, E. and Ori, A. P. and Cantor, R. M. and Vorstman, J. and Strengman, E. and Deyoung, J. and Kappen, T. H. and Pariama, E. and Van Dongen, E. P.A. and Borgdorff, P. and Bruins, P. and De Koning, T. J. and Kahn, R. S. and Ophoff, R. A.}},
  issn         = {{1359-4184}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{12}},
  pages        = {{1557--1564}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Molecular Psychiatry}},
  title        = {{Genome-wide association study of NMDA receptor coagonists in human cerebrospinal fluid and plasma}},
  url          = {{http://dx.doi.org/10.1038/mp.2014.190}},
  doi          = {{10.1038/mp.2014.190}},
  volume       = {{20}},
  year         = {{2015}},
}