Exploring key genes and pathways associated with sex differences in autism spectrum disorder: integrated bioinformatic analysis

Himani Nautiyal; Akanksha Jaiswar; Prabhash Kumar Jha; Shubham Dwivedi

doi:10.1007/s00335-024-10036-5

Exploring key genes and pathways associated with sex differences in autism spectrum disorder: integrated bioinformatic analysis

Mamm Genome. 2024 Apr 9. doi: 10.1007/s00335-024-10036-5. Online ahead of print.

Authors

Himani Nautiyal¹, Akanksha Jaiswar², Prabhash Kumar Jha³, Shubham Dwivedi⁴

Affiliations

¹ Department of Pharmaceutical Sciences, School of Health Sciences and Technology, UPES, Dehradun, 248001, India.
² Laboratory of Human Disease Multiomics, Mossakowski Medical Research Institute Polish Academy of Sciences, Warsaw, Poland.
³ Center for Excellence in Vascular Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Department of Pharmaceutical Sciences, School of Health Sciences and Technology, UPES, Dehradun, 248001, India. Shubham.dwivedi@ddn.upes.ac.in.

PMID: 38594551
DOI: 10.1007/s00335-024-10036-5

Abstract

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder marked by functional abnormalities in brain that causes social and linguistic difficulties. The incidence of ASD is more prevalent in males compared to females, but the underlying mechanism, as well as molecular indications for identifying sex-specific differences in ASD symptoms remain unknown. Thus, impacting the development of personalized strategy towards pharmacotherapy of ASD. The current study employs an integrated bioinformatic approach to investigate the genes and pathways uniquely associated with sex specific differences in autistic individuals. Based on microarray dataset (GSE6575) extracted from the gene expression omnibus, the dysregulated genes between the autistic and the neurotypical individuals for both sexes were identified. Gene set enrichment analysis was performed to ascertain biological activities linked to the dysregulated genes. Protein-protein interaction network analysis was carried out to identify hub genes. The identified hub genes were examined to determine their functions and involvement in the associated pathways using Enrichr. Additionally, hub genes were validated from autism-associated databases and the potential small molecules targeting the hub genes were identified. The present study utilized whole blood transcriptomic gene expression analysis data and identified 2211 and 958 differentially expressed unique genes in males and females respectively. The functional enrichment analysis revealed that male hub genes were functionally associated with RNA polymerase II mediated transcriptional regulation whereas female hub genes were involved in intracellular signal transduction and cell migration. The top male hub genes exhibited functional enrichment in tyrosine kinase signalling pathway. The pathway enrichment analysis of male hub genes indicates the enrichment of papillomavirus infection. Female hub genes were enriched in androgen receptor signalling pathway and functionally enriched in focal adhesion specific excision repair. Identified drug like candidates targeting these genes may serve as a potential sex specific therapeutics. Wortmannin for males, 5-Fluorouracil for females had the highest scores. Targeted and sex-specific pharmacotherapies may be created for the management of ASD. The current investigation identifies sex-specific molecular signatures derived from whole blood which may serve as a potential peripheral sex-specific biomarkers for ASD. The study also uncovers the possible pharmacological interventions against the selected genes/pathway, providing support in development of therapeutic strategies to mitigate ASD. However, experimental proofs on biological systems are warranted.