Fig. 6: Computational drug repurposing analysis via Connectivity Map (cMAP).

AD risk genes are enriched in excitatory neurons. We use the significant AD TWAS associations in excitatory neurons to identify drugs that could potentially reverse the disease gene expressions. CMap Drug clusters are obtained from the L1000FWD study. Each point in the scatter plot represents a drug-induced signature in HT29 cells—chosen for their proximity to excitatory neurons based on Euclidean distances of transcriptome-wide gene expression levels. CMap computes a τ score to quantify the correlation between each query signature and the reference profile, measuring whether the molecule can consistently reverse the gene expression levels of AD risk genes. An empirical one-sided p-value is calculated for each compound, measuring the significance of τ scores (Supplementary Data 20). Points shown as diamonds indicate significant CMap τ scores. Colors represent drug classes based on their mechanism of action. Common drug classes and representative drugs are labeled. The new drug cabergoline, identified for AD treatment, is highlighted as a dopamine receptor agonist.