Drug-targeted Mendelian randomization analysis combined with transcriptome sequencing to explore the molecular
Xixi Wu1,2, Qingyan Yang1,2, Yudi Xie1,2
1The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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.
Insights
This study identifies key genes HNMT, TNFSF8, and S1PR5 involved in cognitive impairment. These genes offer potential new therapeutic targets for developing treatments for cognitive decline and Alzheimer's disease.
Area of Science:
- Genomics
- Neuroscience
- Pharmacology
Background:
- Current therapies for cognitive impairment, including Alzheimer's disease, are limited and can cause adverse effects.
- Understanding the genetic and molecular basis of cognitive decline is crucial for developing targeted treatments.
Purpose of the Study:
- To identify causal genes and potential therapeutic targets for cognitive impairment using integrated genomic analysis.
- To explore genetic links to cognitive decline for novel therapeutic strategies.
Main Methods:
- Integrated genome-wide association study (GWAS) and expression quantitative trait loci (eQTL) data.
- Utilized Mendelian randomization (MR) and SMR colocalization to identify causal genes.
- Performed pathway analysis, immune cell infiltration assessment, and drug target prediction.
Main Results:
- Identified seven significant gene-eQTL pairs associated with cognitive impairment via MR analysis.
- Prioritized HNMT, TNFSF8, and S1PR5 as key genes through SMR colocalization.
- Predicted numerous potential drug targets for these genes, including arsenic trioxide and aspirin.
Conclusions:
- HNMT, TNFSF8, and S1PR5 are implicated as potential therapeutic targets for cognitive impairment.
- These findings suggest novel avenues for drug development for cognitive disorders.
- Further clinical validation is necessary to confirm the therapeutic relevance of these identified genes.
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