Transcriptomic Analysis Reveals Sex-Based Differences in The Prefrontal Cortex of Autism Spectrum Disorder Patients

Objective: The prevalence of neurological disorders often varies by sex, with conditions such as Alzheimer’s diseaseand autism spectrum disorder (ASD) demonstrating notable differences in incidence. The aim of this study is tounderstand the molecular basis for these divergences in order to facilitate the creation of sex-specific therapeutic strategies. Materials and Methods: This study is a bioinformatic analysis of publicly available RNA sequencing datasets involvingautism patients. The study utilized RNA sequencing data from postmortem human brains’ prefrontal cortex, including38 neurotypical controls and 34 individuals with ASD. The sequencing data was obtained from previously publishedpapers, and we downloaded the raw data from SRA. We investigated the molecular basis of sex-biased presentationin ASD through comprehensive transcriptomic analysis. Results: Comparative analysis of gene expression between male and female subjects, both autistic and unaffected,was conducted, using a significance level of ≤0.01. In autistic individuals, 136 genes demonstrated differentialexpression between sexes, predominantly upregulated in males, indicating a bias in male gene expression. Amongthese, 12 genes were identified as risk factors in the SFARI dataset. While most sex-biased genes were autosomal,expression differences on sex chromosomes were also observed in neurotypical subjects. Notable genes includedTCF7L2, collagen family genes, and solute carrier family genes. In ASD males, extracellular matrix (ECM) organizationemerged as a significant pathway, while immune-related processes were prominent in unaffected individuals. Conclusion: Our study highlights the impact of the ECM pathway in ASD, with notable differences between sexes,particularly in males. MIR424 shows promise as a potential biomarker for ASD in males. Recognizing the importanceof sex differences in ASD transcriptomic research is crucial, as these variances provide insights into the disorder’spathophysiology and may guide the development of more personalized treatments for both sexes.