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

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.