A miR-137-related biological pathway of risk for Schizophrenia is associated with human brain emotion processing.

Dorsolateral prefrontal cortex Gene co-expression networks RNA sequencing Schizophrenia emotion processing micro-RNA 137

Journal

Biological psychiatry. Cognitive neuroscience and neuroimaging
ISSN: 2451-9030
Titre abrégé: Biol Psychiatry Cogn Neurosci Neuroimaging
Pays: United States
ID NLM: 101671285

Informations de publication

Date de publication:
22 Nov 2023
Historique:
received: 31 10 2022
revised: 04 11 2023
accepted: 09 11 2023
medline: 25 11 2023
pubmed: 25 11 2023
entrez: 24 11 2023
Statut: aheadofprint

Résumé

MiR-137 is a microRNA involved in brain development, regulating neurogenesis and neuronal maturation. Genome-Wide Association Studies implicate miR-137 in schizophrenia risk but do not explain its involvement in brain function and underlying biology. Polygenic risk for schizophrenia mediated by miR-137 targets is associated with working memory, although other evidence points to emotion processing. We characterized the functional brain correlates of miR-137 target genes associated with schizophrenia while disentangling previously reported associations of miR-137 targets with working memory and emotion processing. Using RNA-sequencing data from postmortem prefrontal cortex (N=522), we identified a co-expression gene set enriched for miR-137 targets and schizophrenia risk genes. We validated the relationship of this set to miR-137 in-vitro by manipulating miR-137 expression in neuroblastoma cells. We translated this gene set into polygenic scores of co-expression prediction and associated them with fMRI activation in healthy volunteers (N In 4,652 human subjects, we found that (i) schizophrenia risk genes are co-expressed in a biologically validated set enriched for miR-137 targets, (ii) increased expression of miR-137 target risk genes is mediated by low prefrontal miR-137 expression, (iii) alleles predicting greater gene-set co-expression are associated with greater prefrontal activation during emotion processing in three independent healthy cohorts (N The functional translation of miR-137 target gene expression linked with schizophrenia involves emotion processing.

Sections du résumé

BACKGROUND BACKGROUND
MiR-137 is a microRNA involved in brain development, regulating neurogenesis and neuronal maturation. Genome-Wide Association Studies implicate miR-137 in schizophrenia risk but do not explain its involvement in brain function and underlying biology. Polygenic risk for schizophrenia mediated by miR-137 targets is associated with working memory, although other evidence points to emotion processing. We characterized the functional brain correlates of miR-137 target genes associated with schizophrenia while disentangling previously reported associations of miR-137 targets with working memory and emotion processing.
METHODS METHODS
Using RNA-sequencing data from postmortem prefrontal cortex (N=522), we identified a co-expression gene set enriched for miR-137 targets and schizophrenia risk genes. We validated the relationship of this set to miR-137 in-vitro by manipulating miR-137 expression in neuroblastoma cells. We translated this gene set into polygenic scores of co-expression prediction and associated them with fMRI activation in healthy volunteers (N
RESULTS RESULTS
In 4,652 human subjects, we found that (i) schizophrenia risk genes are co-expressed in a biologically validated set enriched for miR-137 targets, (ii) increased expression of miR-137 target risk genes is mediated by low prefrontal miR-137 expression, (iii) alleles predicting greater gene-set co-expression are associated with greater prefrontal activation during emotion processing in three independent healthy cohorts (N
CONCLUSIONS CONCLUSIONS
The functional translation of miR-137 target gene expression linked with schizophrenia involves emotion processing.

Identifiants

DOI: 10.1016/j.bpsc.2023.11.001 PMID: 38000716
pubmed: 38000716
pii: S2451-9022(23)00311-7
doi: 10.1016/j.bpsc.2023.11.001
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 Society of Biological Psychiatry. All rights reserved.

Auteurs

Giulio Pergola (G)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 21205 Baltimore, MD, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 21205 Baltimore, MD, USA. Electronic address: giulio.pergola@uniba.it.

Antonio Rampino (A)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy; Azienda Ospedaliero-Universitaria Consorziale Policlinico, 70124 Bari, Italy. Electronic address: antonio.rampino@uniba.it.

Leonardo Sportelli (L)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 21205 Baltimore, MD, USA.

Christopher James Borcuk (CJ)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 21205 Baltimore, MD, USA.

Roberta Passiatore (R)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy; Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, 52428 Jülich, Germany.

Pasquale Di Carlo (P)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy.

Aleksandra Marakhovskaia (A)

Department of Pharmacology, University of Toronto, M5S 1A8 Toronto, Ontario, Canada.

Leonardo Fazio (L)

Department of Medicine and Surgery, Libera Università Mediterranea Giuseppe Degennaro, 70010 Casamassima, Italy.

Nicola Amoroso (N)

Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, 70126 Bari, Italy; Istituto Nazionale di Fisica Nucleare (INFN), Sezione di Bari, 70125 Bari, Italy.

Mariana Nair Castro (MN)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta (Grupo INAAC), Instituto de Neurociencias FLENI-CONICET, 1428 Buenos Aires, Argentina.

Enrico Domenici (E)

Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy; Fondazione The Microsoft Research University of Trento, Centre for Computational and Systems Biology (COSBI), 38068 Rovereto, Italy.

Massimo Gennarelli (M)

Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy.

Jivan Khlghatyan (J)

Azienda Ospedaliero-Universitaria Consorziale Policlinico, 70124 Bari, Italy; Department of Neuroscience, Novartis Institutes for Biomedical Research, Massachusetts, 02139 Cambridge, MA , USA.

Gianluca Christos Kikidis (GC)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 21205 Baltimore, MD, USA.

Annalisa Lella (A)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy.

Chiara Magri (C)

Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.

Alfonso Monaco (A)

Istituto Nazionale di Fisica Nucleare (INFN), Sezione di Bari, 70125 Bari, Italy; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta (Grupo INAAC), Instituto de Neurociencias FLENI-CONICET, 1428 Buenos Aires, Argentina.

Marco Papalino (M)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy.

Madhur Parihar (M)

Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 21205 Baltimore, MD, USA.

Teresa Popolizio (T)

Department of Medicine and Surgery, Libera Università Mediterranea Giuseppe Degennaro, 70010 Casamassima, Italy.

Tiziana Quarto (T)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy; Department of Law, University of Foggia, 71122 Foggia, Italy.

Raffaella Romano (R)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy.

Silvia Torretta (S)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy.

Paolo Valsecchi (P)

Department of Clinical and Experimental Sciences, University of Brescia, 25121 Brescia, Italy; Department of Mental Health and Addiction Services, ASST Spedali Civili of Brescia, 25123 Brescia, Italy.

Hediche Zunuer (H)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy.

Giuseppe Blasi (G)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy; Azienda Ospedaliero-Universitaria Consorziale Policlinico, 70124 Bari, Italy.

Juergen Dukart (J)

Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, 52428 Jülich, Germany; Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, 40223 Düsseldorf, Germany.

Jean Martin Beaulieu (JM)

Department of Pharmacology, University of Toronto, M5S 1A8 Toronto, Ontario, Canada.

Alessandro Bertolino (A)

Group of Psychiatric Neuroscience, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124 Bari, Italy; Azienda Ospedaliero-Universitaria Consorziale Policlinico, 70124 Bari, Italy.

Classifications MeSH