Protective Evidence for Alcohol Consumption in Parkinson’s Disease Risk and Associated Genes of DPP6, SLC39A8, MAD1L1, and RBFOX1

Background Parkinson’s disease (PD), a leading neurodegenerative disorder, is increasing in prevalence globally due to population ageing. Although alcohol consumption is widespread worldwide, its role in PD pathogenesis remains contentious, with studies reporting both protective and harmful associations. Methods Here, we integrate familial, population-based, and genomic data to investigate the relationship between alcohol intake and PD risk. To elucidate causal mechanisms, we performed Mendelian randomization analyses leveraging published genome-wide association study (GWAS) datasets. Results In a three-generation PD pedigree, only the affected individual—who reported abstinence—carried the fewest PD-associated risk variants, while seven unaffected, alcohol-consuming relatives harbored a greater burden of risk variants, suggesting a potential protective effect of alcohol. Population surveys from two Chinese cities revealed significantly lower alcohol consumption among PD patients compared to controls ( P  < 0.01). Cross-national data from 27 countries showed an inverse association between low-to-moderate alcohol intake (< 10 L/capita/year) and PD incidence, whereas heavy consumption (≥ 10 L/capita/year) increased risk. Moderate but frequent alcohol consumption was associated with a reduced genetic risk for PD, potentially mediated by improved sleep quality and mitigating inflammation. Notably, we identified the T-cell surface glycoprotein CD6 isoform as a novel cytokine linking alcohol intake to decreased PD risk, with alcohol consumption reducing circulating CD6 levels. GWAS data further implicated four genes— DPP6 , SLC39A8 , MAD1L1 , and RBFOX1 —in mediating the protective association. Conclusions Together, our findings provide convergent, multi-layered evidence that modified people’s drinking habits may confer protection against PD and highlight potential biological pathways for targeted prevention strategies. Clinical trial number: not applicable.