Identifying potential drug targets for cerebral amyloid angiopathy: A Mendelian randomization study based on the druggable genes

Cerebral amyloid angiopathy (CAA), which is prevalent among older adults, constitutes a major cause of brain hemorrhage, dementia, and cognitive decline. Currently, no effective treatments for alleviating the disease of CAA exist. Hence, the discovery of novel drug targets for CAA is of utmost significance. Cis-expression quantitative trait locus (cis-eQTL) of druggable genes from eQTLGen Consortium and genome-wide association study of CAA from FinnGen database were used to screen for drug-usable genes causally associated with CAA. Robustness was assessed using colocalization analysis and heterogeneity in dependent instruments (HEIDI) tests. Significant findings were further validated using summary-data-based Mendelian randomization (SMR) with blood and arterial tissue eQTL data from eQTLGen and GTEx. Potential drugs targeting prioritized genes were screened using the DSigDB database, and binding interactions were evaluated via molecular docking. Mendelian randomization analysis identified 10 druggable genes significantly associated with CAA risk (false discovery rate < 0.1). Colocalization analysis revealed strong evidence (PPH4 > 0.75) that dipeptidyl peptidase 9 (DPP9) and CAA share a causal genetic variant. DPP9 is a member of the dipeptidyl peptidase IV family and participates in cellular energy metabolism. SMR with HEIDI test confirmed the causal relationship between genetically predicted DPP9 expression and increased CAA risk in both blood (P_SMR < 0.05, P_HEIDI>0.05) and arterial tissues (P_SMR < 0.05, P_HEIDI>0.05). Drug screening identified sitagliptin and zoledronic acid as potential DPP9-targeting compounds. Molecular docking demonstrated a highly favorable binding interaction between sitagliptin and DPP9 (binding energy = -9.0 kcal/mol). This study provides genetic evidence identifying DPP9 as a potential drug target for CAA. The antidiabetic drug sitagliptin, predicted to bind DPP9 with high affinity, represents a promising candidate for therapeutic repurposing in CAA.