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The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis
- Weber, H. (author)
-
- Klamer, Daniel, 1976 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology
- Freudenberg, F. (author)
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- Kittel-Schneider, S. (author)
- Rivero, O. (author)
- Scholz, C. J. (author)
- Volkert, J. (author)
- Kopf, J. (author)
- Heupel, J. (author)
- Herterich, S. (author)
- Alttoa, A. (author)
- Post, A. (author)
- Grussendorf, H. (author)
- Kramer, A. (author)
- Gessner, A. (author)
- Schmidt, B. (author)
- Hempel, S. (author)
- Jacob, C. P. (author)
- Sanjuan, J. (author)
- Molto, M. D. (author)
- Lesch, K. P. (author)
- Freitag, C. M. (author)
- Kent, L. (author)
- Reif, A. (author)
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- (creator_code:org_t)
- Elsevier BV, 2014
- 2014
- English.
- In: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 24:1, s. 65-85
- Journal article (peer-reviewed)
Abstract
Subject headings
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- NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ. interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia. (C) 2013 Elsevier B.V. and ECNP. All rights reserved.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Psykiatri (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Psychiatry (hsv//eng)
Keyword
- Glutamate
- Nitric oxide
- Association
- Schizophrenia
- Post-synapse
- Prefrontal cortex
- NITRIC-OXIDE SYNTHASE
- DYNEIN LIGHT-CHAIN
- CHINESE HAN POPULATION
- TERMINAL PDZ LIGAND
- PREFRONTAL CORTEX
- FAMILIAL SCHIZOPHRENIA
- ALLELIC
- ASSOCIATION
- BIPOLAR DISORDER
- CANDIDATE GENES
- WORKING-MEMORY
- NETICS
- V153B
- P1318
- Glutamate
Publication and Content Type
- ref (subject category)
- art (subject category)
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- Volkert, J.
- Kopf, J.
- Heupel, J.
- Herterich, S.
- Adolfsson, Rolf
- Alttoa, A.
- Post, A.
- Grussendorf, H.
- Kramer, A.
- Gessner, A.
- Schmidt, B.
- Hempel, S.
- Jacob, C. P.
- Sanjuan, J.
- Molto, M. D.
- Lesch, K. P.
- Freitag, C. M.
- Kent, L.
- Reif, A.
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