Drug-targeted Mendelian randomization analysis combined with transcriptome sequencing to explore the molecular mechanisms associated with cognitive impairment.

Abstract

BackgroundCurrent therapies for cognitive impairment, including Alzheimer's disease (AD) and mild cognitive impairment, are limited by a lack of universal treatment and adverse effects associated with polypharmacy. Investigating genetic and molecular mechanisms underlying cognitive decline is critical for the development of targeted therapeutics.ObjectiveTo identify causal genes and potential therapeutic targets for cognitive impairment through integrative genomic analyses.MethodsGenome-wide association study data on cognitive impairment were combined with the expression quantitative trait loci (eQTL) data from the eQTLGen consortium. Mendelian randomization (MR) and colocalization analyses were employed to infer causal relationships. Gene Set Enrichment Analysis and Gene Set Variation Analysis evaluated the pathway and functional differences. Immune cell infiltration patterns and the immunometabolic pathways were assessed, followed by drug target prediction.ResultsMR analysis identified seven gene-eQTL pairs significantly associated with cognitive impairment. SMR colocalization prioritized three key genes: HNMT (histamine metabolism), TNFSF8 (inflammatory signaling), and S1PR5 (sphingolipid signaling). HNMT, TNFSF8, and S1PR5 had 39, 24, and 30 predicted targeted drugs, respectively, including arsenic trioxide, aspirin, and immunomodulators.ConclusionsThis study implicates HNMT, TNFSF8, and S1PR5 as potential therapeutic targets for cognitive impairment. Further validation is required to confirm their clinical relevance.