A Rapamycin Pharmacogenomic Approach for the Childhood Dementia <scp>N</scp> iemann‐ <scp>P</scp> ick C

mice, Rapamycin, an autophagy inductor, yielded opposite results depending on genetic background, suggesting the presence of pharmacogenomic modifiers. To identify them, we used a genotyped yeast panel designed for gene mapping and the NPC-mimetic U18666A (U18-drug) in the presence and absence of rapamycin. We evaluated cell growth, vacuolar fragmentation, and transcriptomics across diverse strains. Linkage analysis based on cell growth identified a significant locus, leading to the prioritization of nine genes. Notably, ccs1 (copper chaperone for superoxide dismutase) and avo2 (TORC2 subunit) deletions decreased cell growth compared to U18-Rapa in WT cells, while irc21 (DNA damage and ceramide metabolism) increased it. Our results suggest that genomic variants within these genes should be assessed before using rapamycin for NPC. This study represents a crucial step towards personalized rapamycin therapeutics.