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Basic Science and Pathogenesis.

Muyang Zhang1, Xiaopu Zhou2

  • 1University of Toronto, Toronto, ON, Canada.

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|December 23, 2025
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Summary
This summary is machine-generated.

Sex differences in gene expression impact brain disorders like Alzheimer's disease (AD) and autism spectrum disorder (ASD). Key genes in synaptic and immune pathways, such as NRXN2 and INPP5D, may drive these sex-specific effects.

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Area of Science:

  • Neurogenetics
  • Molecular Psychiatry
  • Genomics

Background:

  • Sex influences neurodevelopmental and neurodegenerative disease risk, with females more susceptible to Alzheimer's disease (AD) and males to Parkinson's disease and autism spectrum disorder (ASD).
  • The molecular underpinnings of these sex-based disparities in neurological conditions are not well understood.

Purpose of the Study:

  • To identify genes with sex-differential expression in the human brain.
  • To explore the functional pathways and neurological disorder associations of these sex-specific genes.
  • To investigate cell-type-specific expression patterns of identified sex-associated genes.

Main Methods:

  • Analyzed RNA-sequencing data from 2,211 GTEx samples across 13 brain regions.
  • Identified sex-differential expression using robust linear regression and meta-analysis.
  • Performed Gene Ontology analysis and assessed associations with neurological disorders using GWAS Catalog and PsychENCODE data.

Main Results:

  • Identified 2,294 autosomal genes with significant sex-differential expression (p < 0.05, Q_pval < 0.05).
  • 1002 genes were more abundant in females, linked to neural (synapse) and immune (lymphocyte activation) pathways.
  • Specific genes like NRXN2 (ASD-associated) and INPP5D (AD GWAS hit) showed distinct cell-type expression (neurons, microglia, endothelial cells).

Conclusions:

  • Sex-specific gene expression plays a crucial role in brain disorders, including psychiatric conditions and AD.
  • Synaptic and immune pathways, modulated by genes like NRXN2 and INPP5D, are potential drivers of neurological disorder pathophysiology.
  • Findings provide a basis for understanding sex-specific brain function and developing personalized therapies.