W77. GENETIC AND PROTEOGENOMIC INVESTIGATION OF THE SMOKING–PARKINSON’S DISEASE ASSOCIATION
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Le résumé fourni par la source
Background Epidemiologic studies consistently report an inverse association between cigarette smoking and Parkinson’s disease (PD), yet the biological mechanisms underlying this relationship remain unclear. To investigate the causal and molecular basis of this association, we integrated genomic and proteogenomic analyses across smoking-related traits and PD. Methods We analyzed genome-wide association study (GWAS) summary statistics for smoking initiation, cigarettes per day, nicotine metabolism, and PD. Two-sample Mendelian randomization (MR) was used to test whether genetic liability to smoking behaviors influences PD risk. Shared genetic architecture was quantified using MiXeR, and conjunctional false discovery rate (conjFDR) analysis identified loci jointly associated with smoking and PD. To investigate downstream molecular mechanisms, we integrated dorsolateral prefrontal cortex proteomic data with GWAS using proteome-wide association studies (PWAS), summary-based Mendelian randomization, heterogeneity testing, and colocalization analyses. Results MR analyses indicated a protective association between genetic liability to smoking initiation and PD risk (OR = 0.78, 95% CI: 0.67–0.91), whereas cigarettes per day and nicotine metabolism showed no causal association with PD. Polygenic modeling revealed modest genetic overlap between smoking initiation and PD with predominantly discordant variant effects. ConjFDR analyses identified 95 shared loci linked to genes enriched in PD-relevant brain regions, including the substantia nigra and basal ganglia. Integration with brain proteomic data identified 11 overlapping risk proteins, implicating neurotrophic signaling, synaptic organization, microglial modulation, and mitochondrial stress response pathways. Several proteins—including AKT3, MAPT, and RIT2—were supported by both genomic and proteomic evidence and represent biologically plausible therapeutic targets. Discussion These findings suggest that genetic liability to smoking initiation is associated with modest protection against PD and highlight convergent molecular pathways that may mediate this relationship. By integrating genetic and proteomic data, this work provides insight into the biological basis of the smoking–PD association and identifies candidate targets for developing smoke-free neuroprotective strategies.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- W77. GENETIC AND PROTEOGENOMIC INVESTIGATION OF THE SMOKING–PARKINSON’S DISEASE ASSOCIATION
- Date Crossref
- 01/10/2026
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
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Uniformed Services University of the Health Sciences, Emory and Henry College et University of California, avec 7 autres affiliations.
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