RT Journal Article SR Electronic T1 Sex differences in the human brain transcriptome of cases with schizophrenia JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.10.05.326405 DO 10.1101/2020.10.05.326405 A1 Gabriel E. Hoffman A1 Yixuan Ma A1 Kelsey S. Montgomery A1 Jaroslav Bendl A1 Manoj Kumar Jaiswal A1 Alex Kozlenkov A1 the CommonMind Consortium A1 Mette A. Peters A1 Stella Dracheva A1 John F. Fullard A1 Andrew Chess A1 Bernie Devlin A1 Solveig K. Sieberts A1 Panos Roussos YR 2020 UL http://biorxiv.org/content/early/2020/10/07/2020.10.05.326405.abstract AB While schizophrenia differs between males and females in age of onset, symptomatology and the course of the disease, the molecular mechanisms underlying these differences remain uncharacterized. In order to address questions about the sex-specific effects of schizophrenia, we performed a large-scale transcriptome analysis of RNA-seq data from 437 controls and 341 cases from two distinct cohorts from the CommonMind Consortium. Analysis across the cohorts identifies a reproducible gene expression signature of schizophrenia that is highly concordant with previous work. Differential expression across sex is reproducible across cohorts and identifies X- and Y-linked genes, as well as those involved in dosage compensation. Intriguingly, the sex expression signature is also enriched for genes involved in neurexin family protein binding and synaptic organization. Differential expression analysis testing a sex-by-diagnosis interaction effect did not identify any genome-wide signature after multiple testing corrections. Gene coexpression network analysis was performed to reduce dimensionality and elucidate interactions among genes. We found enrichment of co-expression modules for sex-by-diagnosis differential expression signatures, which were highly reproducible across the two cohorts and involve a number of diverse pathways, including neural nucleus development, neuron projection morphogenesis, and regulation of neural precursor cell proliferation. Overall, our results indicate that the effect size of sex differences in schizophrenia gene expression signatures is small and underscore the challenge of identifying robust sex-by-diagnosis signatures, which will require future analyses in larger cohorts.Competing Interest StatementThe authors have declared no competing interest.