A Multilevel Functional Study of a SNAP25 At-Risk Variant for Bipolar Disorder and Schizophrenia

Publikationstyp:
Zeitschriftenaufsatz
Metadaten:
Autoren
  • Josselin Houenou
  • Jennifer Boisgontier
  • Annabelle Henrion
  • Marc-Antoine d'Albis
  • Anne Dumaine
  • Julia Linke
  • Michele Wessa
  • Claire Daban
  • Nora Hamdani
  • Marine Delavest
  • Pierre-Michel Llorca
  • Christophe Lancon
  • Franck Schurhoff
  • Andrei Szoke
  • Philippe Le Corvoisier
  • Caroline Barau
  • Cyril Poupon
  • Bruno Etain
  • Marion Leboyer
  • Stephane Jamain
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000413745200011&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1523/JNEUROSCI.1040-17.2017
Externe Identifier
  • Clarivate Analytics Document Solution ID: FK8GE
  • PubMed Identifier: 28972123
ISSN
0270-6474
Ausgabe der Veröffentlichung
43
Zeitschrift
JOURNAL OF NEUROSCIENCE
Schlüsselwörter
  • bipolar disorder
  • brain imaging
  • genetics
  • schizophrenia
  • SNAP25
  • SNARE
Paginierung
10389 - 10397
Datum der Veröffentlichung
2017
Status
Published
Titel
A Multilevel Functional Study of a <i>SNAP25</i> At-Risk Variant for Bipolar Disorder and Schizophrenia
Sub types
  • Article
Ausgabe der Zeitschrift
37

Datenquelle: Web of Science (Lite)

Andere Metadatenquellen:
Abstract
<jats:p>The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in<jats:italic>SNAP25</jats:italic>,<jats:italic>rs6039769</jats:italic>, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined<jats:italic>in vitro</jats:italic>and<jats:italic>in vivo</jats:italic>approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed<jats:italic>in vitro</jats:italic>that the<jats:italic>rs6039769</jats:italic>C allele was sufficient to increase the<jats:italic>SNAP25</jats:italic>transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the<jats:italic>SNAP25b</jats:italic>/<jats:italic>SNAP25a</jats:italic>ratio was increased in schizophrenic patients carrying the<jats:italic>rs6039769</jats:italic>at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala–ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of<jats:italic>SNAP25</jats:italic>on modulating the development and plasticity of the prefrontal–limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia.</jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT</jats:bold>Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of<jats:italic>SNAP25</jats:italic>on modulating the development and plasticity of the prefrontal–limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.</jats:p>
Autoren
  • Josselin Houenou
  • Jennifer Boisgontier
  • Annabelle Henrion
  • Marc-Antoine d'Albis
  • Anne Dumaine
  • Julia Linke
  • Michèle Wessa
  • Claire Daban
  • Nora Hamdani
  • Marine Delavest
  • Pierre-Michel Llorca
  • Christophe Lançon
  • Franck Schürhoff
  • Andrei Szöke
  • Philippe Le Corvoisier
  • Caroline Barau
  • Cyril Poupon
  • Bruno Etain
  • Marion Leboyer
  • Stéphane Jamain
DOI
10.1523/jneurosci.1040-17.2017
eISSN
1529-2401
ISSN
0270-6474
Ausgabe der Veröffentlichung
43
Zeitschrift
The Journal of Neuroscience
Sprache
en
Online publication date
2017
Paginierung
10389 - 10397
Datum der Veröffentlichung
2017
Status
Published
Herausgeber
Society for Neuroscience
Herausgeber URL
http://dx.doi.org/10.1523/jneurosci.1040-17.2017
Datum der Datenerfassung
2023
Titel
A Multilevel Functional Study of a<i>SNAP25</i>At-Risk Variant for Bipolar Disorder and Schizophrenia
Ausgabe der Zeitschrift
37

Datenquelle: Crossref

Abstract
The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in <i>SNAP25</i>, <i>rs6039769</i>, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined <i>in vitro</i> and <i>in vivo</i> approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed <i>in vitro</i> that the <i>rs6039769</i> C allele was sufficient to increase the <i>SNAP25</i> transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the <i>SNAP25b</i>/<i>SNAP25a</i> ratio was increased in schizophrenic patients carrying the <i>rs6039769</i> at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of <i>SNAP25</i> on modulating the development and plasticity of the prefrontal-limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia.<b>SIGNIFICANCE STATEMENT</b> Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of <i>SNAP25</i> on modulating the development and plasticity of the prefrontal-limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.
Addresses
  • INSERM U955, Institut Mondor de Recherches Biomédicales, Psychiatrie Translationnelle, F-94000 Créteil, France.
Autoren
  • Josselin Houenou
  • Jennifer Boisgontier
  • Annabelle Henrion
  • Marc-Antoine d'Albis
  • Anne Dumaine
  • Julia Linke
  • Michèle Wessa
  • Claire Daban
  • Nora Hamdani
  • Marine Delavest
  • Pierre-Michel Llorca
  • Christophe Lançon
  • Franck Schürhoff
  • Andrei Szöke
  • Philippe Le Corvoisier
  • Caroline Barau
  • Cyril Poupon
  • Bruno Etain
  • Marion Leboyer
  • Stéphane Jamain
DOI
10.1523/jneurosci.1040-17.2017
eISSN
1529-2401
Externe Identifier
  • PubMed Identifier: 28972123
  • PubMed Central ID: PMC6596626
Open access
false
ISSN
0270-6474
Ausgabe der Veröffentlichung
43
Zeitschrift
The Journal of neuroscience : the official journal of the Society for Neuroscience
Schlüsselwörter
  • Limbic System
  • Prefrontal Cortex
  • Nerve Net
  • Cell Line, Tumor
  • Animals
  • Humans
  • Mice
  • Genetic Predisposition to Disease
  • Magnetic Resonance Imaging
  • Bipolar Disorder
  • Schizophrenia
  • Adult
  • Middle Aged
  • Female
  • Male
  • Synaptosomal-Associated Protein 25
  • Genetic Variation
  • Young Adult
Sprache
eng
Medium
Print-Electronic
Online publication date
2017
Paginierung
10389 - 10397
Datum der Veröffentlichung
2017
Status
Published
Publisher licence
CC BY-NC-SA
Datum der Datenerfassung
2017
Titel
A Multilevel Functional Study of a <i>SNAP25</i> At-Risk Variant for Bipolar Disorder and Schizophrenia.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
37

Files

https://www.jneurosci.org/content/jneuro/37/43/10389.full.pdf https://europepmc.org/articles/PMC6596626?pdf=render

Datenquelle: Europe PubMed Central

Abstract
The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in SNAP25, rs6039769, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined in vitro and in vivo approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed in vitro that the rs6039769 C allele was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the SNAP25b/SNAP25a ratio was increased in schizophrenic patients carrying the rs6039769 at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia.SIGNIFICANCE STATEMENT Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.
Date of acceptance
2017
Autoren
  • Josselin Houenou
  • Jennifer Boisgontier
  • Annabelle Henrion
  • Marc-Antoine d'Albis
  • Anne Dumaine
  • Julia Linke
  • Michèle Wessa
  • Claire Daban
  • Nora Hamdani
  • Marine Delavest
  • Pierre-Michel Llorca
  • Christophe Lançon
  • Franck Schürhoff
  • Andrei Szöke
  • Philippe Le Corvoisier
  • Caroline Barau
  • Cyril Poupon
  • Bruno Etain
  • Marion Leboyer
  • Stéphane Jamain
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/28972123
DOI
10.1523/JNEUROSCI.1040-17.2017
eISSN
1529-2401
Externe Identifier
  • PubMed Central ID: PMC6596626
Ausgabe der Veröffentlichung
43
Zeitschrift
J Neurosci
Schlüsselwörter
  • SNAP25
  • SNARE
  • bipolar disorder
  • brain imaging
  • genetics
  • schizophrenia
  • Adult
  • Animals
  • Bipolar Disorder
  • Cell Line, Tumor
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Limbic System
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Middle Aged
  • Nerve Net
  • Prefrontal Cortex
  • Schizophrenia
  • Synaptosomal-Associated Protein 25
  • Young Adult
Sprache
eng
Country
United States
Paginierung
10389 - 10397
PII
JNEUROSCI.1040-17.2017
Datum der Veröffentlichung
2017
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2017
Titel
A Multilevel Functional Study of a SNAP25 At-Risk Variant for Bipolar Disorder and Schizophrenia.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
37

Datenquelle: PubMed

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