A miR-137–Related Biological Pathway of Risk for Schizophrenia Is Associated With Human Brain Emotion Processing

• Autores: Pergola, Giulio; Rampino, Antonio; Sportelli, Leonardo; Borcuk, Christopher James; Passiatore, Roberta; Di Carlo, Pasquale; Marakhovskaia, Aleksandra; Fazio, Leonardo; Amoroso, Nicola; Castro, Mariana Nair; Domenici, Enrico; Gennarelli, Massimo; Khlghatyan, Jivan; Christos Kikidis, Gianluca; Lella, Annalisa; Magri, Chiara; Monaco, Alfonso; Papalino, Marco; Parihar, Madhur; Popolizio, Teresa; Quarto, Tiziana; Romano, Raffaella; Torretta, Silvia; Valsecchi, Paolo; Zunuer, Hediche; Blasi, Giuseppe; Dukart, Juergen; Beaulieu, Jean Martin; Bertolino, Alessandro
• Año de publicación: 2023
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: DLPFC; GENE CO-EXPRESSION NETWORKS; RNA SEQUENCING; SCHIZOPHRENIA; EMOTION PROCESSING; MICRO-RNA 137
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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: 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 (N1=214; N2=136; N3=2,075; N4=1,800) and with short-term treatment response in patients with schizophrenia (N=427).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 (N1-2-3), in interaction with age (N4), (iv) these alleles predict less improvement in negative symptoms following antipsychotic treatment in patients with schizophrenia.Conclusions: The functional translation of miR-137 target gene expression linked with schizophrenia involves emotion processing.
Fil: Pergola, Giulio. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Rampino, Antonio. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Sportelli, Leonardo. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Borcuk, Christopher James. Lieber Institute For Brain Development; Estados Unidos
Fil: Passiatore, Roberta. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Di Carlo, Pasquale. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Marakhovskaia, Aleksandra. University of Toronto; Canadá
Fil: Fazio, Leonardo. No especifíca;
Fil: Amoroso, Nicola. Istituto Nazionale Di Fisica Nucleare.; Italia
Fil: Castro, Mariana Nair. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia. Instituto de Neurociencias - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Neurociencias; Argentina
Fil: Domenici, Enrico. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Gennarelli, Massimo. University Of Brescia; Italia
Fil: Khlghatyan, Jivan. Novartis Institutes for Biomedical Research; Estados Unidos
Fil: Christos Kikidis, Gianluca. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Lella, Annalisa. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Magri, Chiara. University Of Brescia; Italia
Fil: Monaco, Alfonso. Istituto Nazionale Di Fisica Nucleare.; Italia
Fil: Papalino, Marco. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Parihar, Madhur. Lieber Institute For Brain Development; Estados Unidos
Fil: Popolizio, Teresa. No especifíca;
Fil: Quarto, Tiziana. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Romano, Raffaella. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Torretta, Silvia. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Valsecchi, Paolo. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Zunuer, Hediche. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Blasi, Giuseppe. Università Degli Studi Di Bari Aldo Moro; Italia
Fil: Dukart, Juergen. Heinrich Heine University Düsseldorf; Alemania
Fil: Beaulieu, Jean Martin. University of Toronto; Canadá
Fil: Bertolino, Alessandro. Università Degli Studi Di Bari Aldo Moro; Italia