Analysis Proposal
Analysis Question
Can we validate the relationship between PVALB gene expression changes and neurodegeneration phenotypes across multiple independent datasets?
Datasets
GTEx brain tissue RNA-seq expression dataAllen Brain Atlas single-cell RNA-seq datasetsGWAS Catalog neurodegenerative disease lociADNI (Alzheimer's Disease Neuroimaging Initiative) proteomics data
Methods
Differential gene expression analysis comparing PVALB levels in affected vs unaffected brain regions using linear modelsGene set enrichment analysis testing PVALB in neurodegenerative disease-related modulesNetwork propagation analysis on protein-protein interaction networks to assess connectivity to known neurodegeneration genesCausal inference testing using_summary-data-based Mendelian randomization (SMR) with GWAS summary statistics
Expected Outputs
- Log2 fold-change and adjusted p-value for PVALB expression in substantia nigra, hippocampus, and motor cortex across ALS, Parkinson's, and Alzheimer's cohorts; significant downregulation would support the relationship
- Enrichment odds ratio and FDR for PVALB within neurodegeneration-associated co-expression modules; connectivity would indicate shared regulatory mechanisms
- Propagation significance score and z-statistic measuring network proximity from PVALB to established neurodegeneration genes (e.g., SNCA, LRRK2, MAPT); proximity would corroborate functional relationship
- SMR beta and p-value testing pleiotropic colocalization; significant results would indicate shared genetic architecture supporting causal implication