Integrative transcriptomics reveals sexually dimorphic microRNA control of the cholinergic/neurokine interface in schizophrenia and bipolar disorder.
Lobentanzer et al. show how bioinformatically supported high-throughput techniques such as short RNA sequencing can bridge the gap between traditional molecular interaction studies and purely bioinformatic prediction paradigms in an example focused on disentangling the sexual dimorphism in microRNA regulation of the cholinergic/neurokine interface in mental disease. Summary: RNA-sequencing analyses are often limited to identifying lowest p-value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA-sequencing of human male- and female-originated cell lines, and connectomics of transcription factor- and microRNA-interactions with perturbed transcripts. We used this pipeline to analyze cortical transcripts of schizophrenia and bipolar disorder patients. While these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphism remained unexplained. Our method allowed us to disentangle the differences between diseasaffectedafflicted men and women and identified the disease-affected pathways of cholinergic transmission and gp130-family neurokine controllers of immune function, interlinked by microRNAs. This approach may open new perspectives for seeking biomarkers and therapeutic targets, also in other transmitter systems and diseases.