Sex Differences in the Human Brain Transcriptome of Cases With Schizophrenia

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Schizophrenia exhibits distinct characteristics between males and females, including age of onset, symptoms, and disease progression.
• The molecular underpinnings of these sex-specific differences in schizophrenia remain largely uncharacterized.

Purpose of the Study:

• To investigate sex-specific effects in schizophrenia by analyzing transcriptome data.
• To identify reproducible gene expression signatures associated with sex differences in schizophrenia.

Main Methods:

• Performed large-scale transcriptome analysis using RNA sequencing data from two distinct cohorts (CommonMind Consortium).
• Analyzed data from 437 controls and 341 schizophrenia cases.
• Utilized gene coexpression network analysis to identify module enrichment for sex-by-diagnosis differential expression signatures.

Main Results:

• Identified reproducible gene expression signatures for schizophrenia, consistent with prior research.
• Found reproducible differential gene expression across sexes, including X- and Y-linked genes and those involved in dosage compensation.
• Observed enrichment of sex expression signatures in genes related to neurexin family protein binding and synaptic organization. Sex-by-diagnosis interaction effects were not genome-wide significant.
• Gene coexpression network analysis revealed enrichment of modules associated with sex-by-diagnosis signatures, involving pathways like neural development and synaptic organization.

Conclusions:

• The effect size of sex differences in schizophrenia gene expression signatures is generally small.
• Identifying robust sex-by-diagnosis signatures presents a challenge, necessitating larger cohort analyses in the future.