MIR1255A regulates pathways critical for brain development, risk genes for depression and neurodevelopmental disorders

Multiple lines of evidence implicate microRNAs (miRNAs) in major depressive disorder (MDD), including the location of miRNAs genes (MIRs) within genomic regions identified by genome wide association studies (GWAS). To investigate the role of MIRs in the genetic risk for MDD, we identified all associated single nucleotide polymorphism (SNPs) that were expression quantitative loci (eQTLs) for MIRs in brain tissues. Our analyses identified four MIRs having associated eQTLs in the credible SNP set (variants near a genetic association signal predicted to include causal variants). Based on pathway analyses of the predicted targets, we selected MIR1255A for functional studies and overexpressed it in human neural precursor cells (NPCs) to identify target genes in neural cells. Transcriptome analyses of the transfected cells identified 343 differentially expressed (DE) genes at an adjusted p (FDR) <0.05 and an additional 276 DE genes at adjusted p < 0.1 (total 619 genes). Of these, 14 genes were supported as genetic risk genes by fine mapping by GWAS (representation factor 1.8, p < 0.025), with additional genes implicated in risk from biological studies (altered expression or serum levels in individuals with MDD, animal models). Notably, 157 DE genes were implicated in neurodevelopmental disorders (representation factor 1.5, p < 3.31E-07). Gene set enrichment analyses of DE genes revealed the top categories as neurogenesis, generation of neurons, regulation of cell differentiation and neuron development. These findings support MIR1255A as regulator of processes critical for neurodevelopment and a contributor to genetic risk for depression.