A miR-137–Related Biological Pathway of Risk for Schizophrenia Is Associated With Human Brain Emotion Processing
Giulio Pergola, Antonio Rampino, Leonardo Sportelli, Christopher Borcuk, Roberta Passiatore, Pasquale Di Carlo, Aleksandra Marakhovskaia, Leonardo Fazio, Nicola Amoroso, Mariana N. Castro, Enrico Domenici, Massimo Gennarelli, Jivan Khlghatyan, Gianluca Christos Kikidis, Annalisa Lella, Chiara Magri, A. Monaco, Marco Papalino, Madhur Parihar, Teresa Popolizio, Tiziana Quarto, Raffaella Romano, Silvia Torretta, Paolo Valsecchi, Hailiqiguli Zunuer, Giuseppe Blasi, Juergen Dukart, Jean‐Martin Beaulieu, Alessandro Bertolino
Abstract
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 (N1=214; N2=136; N3=2,075; N4=1,800) and with short-term treatment response in patients with schizophrenia (N=427). 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. The functional translation of miR-137 target gene expression linked with schizophrenia involves emotion processing.