Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder

Cell Rep. 2019 Oct 15;29(3):764-777.e5. doi: 10.1016/j.celrep.2019.09.017. | PubMed

Sebastian Lobentanzer¹, Geula Hanin², Jochen Klein¹, Hermona Soreq³

1. Department of Pharmacology, College of Pharmacy, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
2. The Edmond and Lily Safra Center for Brain Science and the Life Sciences Institute, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
3. The Edmond and Lily Safra Center for Brain Science and the Life Sciences Institute, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address: hermona.soreq@mail.huji.ac.il.

Abstract

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-originating 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. Although these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphisms remain unexplained. Our method reveals the differences between afflicted men and women and identifies disease-affected pathways of cholinergic transmission and gp130-family neurokine controllers of immune function interlinked by microRNAs. This approach may open additional perspectives for seeking biomarkers and therapeutic targets in other transmitter systems and diseases.

Presented By Hermona Soreq