Abstract
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>BACKGROUND</jats:title> <jats:p> The persistent puzzle of how <jats:italic>GBA1</jats:italic> coding variants underlying monogenic Gaucher disease confer such strong risk for polygenic Parkinson’s disease (PD) remains unresolved. Here, we sought to resolve this long-standing paradox. </jats:p> </jats:sec> <jats:sec> <jats:title>METHODS</jats:title> <jats:p>Using the Parkinson’s Progression Markers Initiative resource, we integrated whole-genome sequencing from sporadic PD cases and controls with matched transcriptomic, epigenomic and cerebrospinal fluid proteomic data across Northern European and Ashkenazi Jewish populations. Ancestry-specific genetic maps enabled precise integration of disease localisation with eQTL, pQTL and chromatin architecture, linking genetic association to molecular mechanism, while evolutionary genetic analyses resolved the regional haplotypic architecture.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p> We identified a PD-associated regulatory signal located 150 kilobases distal to <jats:italic>GBA1</jats:italic> that robustly replicated across all molecular datasets and both ancestries. Integrative mapping identified rs77268551-G as the candidate regulatory variant, which we show resides on an extended haplotype also carrying the Gaucher disease-causing N370S allele. Evolutionary analyses reveal a clear signature of recent positive selection acting on the Gaucher disease-causing N370S allele, giving rise to this extended shared haplotype that likely concealed the underlying distal PD-associated regulatory signal. rs77268551-G resides within a neuronal enhancer with features consistent with super-enhancer activity that orchestrates hierarchical enhancer-to-enhancer-to-promoter interactions with eleven <jats:italic>cis</jats:italic> -target genes, including <jats:italic>ADAR</jats:italic> , <jats:italic>IL6R</jats:italic> and <jats:italic>GBA1</jats:italic> , driving a coordinated transcriptional programme. Proteomic profiling identified genotype-specific cerebrospinal fluid protein signatures, including PARK7, BIN1 and SAA1, consistent with a neuroinflammatory programme. </jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSIONS</jats:title> <jats:p> The findings support a dual-hit model in which a distal regulatory element is the primary driver of PD-associated molecular programmes, while co-inherited <jats:italic>GBA1</jats:italic> protein-coding variation on the same haplotype modifies and amplifies the risk established by the regulatory variant, giving rise to the clinically distinct <jats:italic>GBA1</jats:italic> -associated PD phenotype. Regulatory activation and <jats:italic>GBA1</jats:italic> -related functional effects converge on neuroinflammatory and lysosomal pathways, and the resulting molecular signatures suggest genotype-linked biomarkers with potential clinical relevance. </jats:p> </jats:sec>