ArticleMammalian genome : official journal of the International Mammalian Genome Society2025
Integrative multiomics elucidate crotonylation-associated GCDH in Parkinson's disease pathogenesis via metabolome remodeling.
Article in Mammalian genome : official journal of the International Mammalian Genome Society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
The pathophysiological significance of crotonylation and its metabolomic regulatory circuitry in Parkinson's disease (PD) remains elusive. We utilized Mendelian randomization (MR) frameworks combined with mediation analysis to establish causal links between crotonylation-associated genes and PD, while systematically delineating metabolite-mediated mechanisms. In this study, crotonylation-related genes were selected from the eQTLGen dataset, and their causal relationship with PD was assessed using two-sample MR analysis. Subsequently, we investigated metabolites associated with PD risk. Additionally, two-step MR and MR mediation analyses were applied to explore the mediating effects of crotonylation-related genes, metabolites, and PD. To further interpret cellular heterogeneity, publicly available GEO single-cell transcriptome data were integrated to analyze PD brain tissue dynamics and the regulatory mechanisms of key crotonylation-related genes. We identified 16 crotonylation-associated genes harboring cis-eQTLs, notably SIRT1, GCDH, and HDAC7, which demonstrated significant inverse associations with PD risk (p < 0.05). Through MR analysis, 74 PD-associated metabolites were identified. Mediation analysis further delineated GCDH-mediated PD risk reduction (β
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