The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: further evidence and meta-analysis.
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.
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany; Microarray Core Unit, IZKF Würzburg, University Hospital of Würzburg, Germany.
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H
Weber
Department of Pharmacology, The Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden.
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D
Klamer
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
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F
Freudenberg
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
S
S
Kittel-Schneider
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany; CIBERSAM, Universitat de Valencia, Valencia, Spain.
O
O
Rivero
Microarray Core Unit, IZKF Würzburg, University Hospital of Würzburg, Germany.
C-J
CJ
Scholz
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
J
J
Volkert
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
J
J
Kopf
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
J
J
Heupel
Comprehensive Heart Failure Center, University of Würzburg, Germany.
S
S
Herterich
Department of Clinivcal Sciences, Psychiatry, Umeå University, Sweden.
R
R
Adolfsson
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
A
A
Alttoa
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
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A
Post
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
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H
Grußendorf
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
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A
Kramer
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
A
A
Gessner
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
B
B
Schmidt
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
S
S
Hempel
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany.
C P
CP
Jacob
CIBERSAM, Universitat de Valencia, Valencia, Spain.
J
J
Sanjuán
CIBERSAM, Universitat de Valencia, Valencia, Spain.
M D
MD
Moltó
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany; Comprehensive Heart Failure Center, University of Würzburg, Germany.
K-P
KP
Lesch
Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University of Frankfurt, Germany.
C M
CM
Freitag
School of Medicine, University of St Andrews, Scotland, UK.
L
L
Kent
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany; Comprehensive Heart Failure Center, University of Würzburg, Germany. Electronic address: reif_a@klinik.uni-wuerzburg.de.
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Reif
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019295:Computational Biology; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000235:genetics* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017397:Prefrontal Cortex / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics*; D013569:Synapses / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C488081:NOS1AP protein, human; D009569:Nitric Oxide; D018698:Glutamic Acid; D052248:Nitric Oxide Synthase Type I
Association; Glutamate; Nitric oxide; Post-synapse; Prefrontal cortex; Schizophrenia