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| 001 | 1019094 | ||
| 005 | 20250204113740.0 | ||
| 024 | 7 | _ | |a 10.1016/j.bpsc.2023.11.001 |2 doi |
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| 100 | 1 | _ | |a Pergola, Giulio |0 P:(DE-HGF)0 |b 0 |e Corresponding author |
| 245 | _ | _ | |a A miR-137-related biological pathway of risk for Schizophrenia is associated with human brain emotion processing |
| 260 | _ | _ | |a Amsterdam [u.a.] |c 2024 |b Elsevier Inc. |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 520 | _ | _ | |a BackgroundMiR-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.MethodsUsing 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).ResultsIn 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. |
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