Identifying transcriptional signatures in Multiple Sclerosis (MS) that may predispose female-biased disease presentation.

MS has increased rates of presentation in females as compared to males. Current research into the underlying cause of female-biased presentation of autoimmune diseases focuses on genetic loci and hormonal differences that differ between males and females and predispose dysregulated immunologic states. Genes on the X chromosome may escape lyonization, allowing increased genetic dosage of immune-regulating genes to drive disease states in genotypically XX individuals. 

To investigate X chromosome escape, RNAseq data of 38 MS patients as well as 26 age and gender-matched controls from publicly available data sets were analyzed for differential gene expression on autosomes and the X chromosome. Our workflows utilized in-house custom scripts as well as the EdgeR Bioconductor package to interrogate differential gene expression signatures across chromosomal makeup and disease state. Gene set enrichment and pathway analyses were further conducted on sex specific differentially expressed genes.

We identified sets of 117 female-specific, 114 male-specific, and 66 mutual differentially expressed X chromosome genes in patients with MS. Gene set enrichment analyses of female-specific MS genes implicates toll like receptor (TLR) genes including TLR7 and TLR8 and pathway analyses further points to toll like receptor cascades as well as immune signaling by interleukins and cytokine receptors. Other genes with high effect sizes in our analyses suggest GPCR signaling, underscoring the need for novel avenues of therapeutic target development.

Differential gene expression demonstrates unique patterns of gene expression for males and females affected by MS. Identification of gene sets that stratify by X-chromosomal makeup (XX or XY) demonstrate differing patterns of genetic dysregulation. Genes identified from the analysis may play a role in autoimmune phenotypes and characterizing these genetic loci provides insight toward the topography of the X chromosome in MS.