Objective: To assess how genetic variation in GALC influences the risk of Parkinson’s disease (PD).

Background: Genome-wide association studies (GWAS) in PD have identified a locus on chromosome 14, with GALC implicated as the gene driving the association. GALC encodes the lysosomal enzyme galactosylceramidase, a key component of the glycosphingolipid metabolism pathway. However, the causal variants and mechanisms through which this locus influences PD risk remain unclear.

Method: We performed GCTA-COJO at the GALC locus using the latest PD GWAS dataset (63,555 cases, 17,700 proxy cases, and 1,746,386 controls) to identify independent association signals. We then conducted fine-mapping analyses using FINEMAP and SuSiE to prioritize potential causal variants. To evaluate whether the PD GWAS shared a genetic basis with gene expression, we performed colocalization analysis using COLOC with eQTL data from 13 brain tissues (n = 181–300, GTEx). Finally, we conducted SMR analysis using cortex eQTL data (n = 2,865, MetaBrain) to further test for associations between gene expression and disease risk.

Results: GCTA-COJO identified a single independent association signal at the GALC locus represented by rs979812 (β = 0.0439, SE = 0.00672, P = 6.49 × 10⁻¹¹). Fine-mapping analyses converged on a credible set of nine potential causal variants, with rs979812 ranked as the top candidate. Colocalization analyses identified a shared genetic signal between the PD lead variant rs979812 and the eQTL variant rs8005172 (R_{EUR}^2 = 1) in the brain anterior cingulate cortex (ACC). SMR analysis revealed a significant association between GALC expression in brain cortex and PD risk, with rs400777 as the top instrumental variant (Pₛₘᵣ = 6.30 × 10⁻⁷, β = 0.128, SE = 0.0257).

Conclusion: Our findings suggest that the association of variants in the GALC locus with PD may be driven by their effect on increasing galactosylceramidase expression, supporting a mechanism mediated by common regulatory variation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/investigating-the-genetic-effect-of-galc-in-parkinsons-disease/