Brain Transcriptome Analysis Identifies Sex‐Associated Synaptic and Immune‐Associated Genes Involved in Alzheimer's Disease and Psychiatric Disorders
Bibliographic record
Abstract
BACKGROUND: Sex differences significantly influence the risk and progression of neurodevelopmental and neurodegenerative disorders. Females exhibit higher susceptibility to Alzheimer's disease (AD), while males are more prone to Parkinson's disease and autism spectrum disorder (ASD). Despite these observations, the molecular mechanisms driving these sex differences remain poorly understood. METHOD: RNA-seq data from 2,211 samples spanning 13 brain regions and 980 individuals were obtained from the GTEx database. Autosomal genes with sex-differential expression were identified using robust linear regression, followed by meta-analysis. Genes meeting the significance thresholds (p < 0.05 and Q_pval < 0.05) were subjected to Gene Ontology analysis to explore their biological functions. Associations with neurological disorders were assessed using annotations from the GWAS Catalog. Single-cell RNA-seq data from the PsychENCODE Knowledge Portal (syn25922167) were analyzed to investigate the cell-type-specific expression patterns of the identified genes. RESULT: A total of 2,294 genes met the significance criteria (p < 0.05 and Q_pval < 0.05). Among autosomal genes with sex-differential expression, 1002 were more abundant in females and were primarily associated with neural-related pathways (e.g., synapse; p = 9.61 × 10⁻¹⁰) and immune-related pathways (e.g., lymphocyte activation; p = 3.99 × 10⁻²). Several of these neural and immune-associated genes are linked to several psychiatric disorders and AD. For instance, synaptic genes such as NRXN2 and CNTNAP2 are associated with ASD, while INPP5D, an AD GWAS hit involved in lymphocyte activation, stands out. Single-cell RNA-seq analysis revealed cell-type-specific expression patterns of these sex-associated genes. For example, INPP5D is predominantly expressed in microglia and endothelial cells, whereas NRXN2 is expressed in both excitatory and inhibitory neurons. CONCLUSION: This study highlights the critical role of sex-specific gene expression in brain disorders, particularly psychiatric disorders and AD. Synaptic and immune-associated pathways, mediated by key sex-associated genes such as NRXN2 and INPP5D, emerge as potential modulators of neurological disorders. These findings deepen our understanding of sex-specific brain pathophysiology and offer a foundation for developing personalized therapeutic strategies targeting these mechanisms.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".