Objective: To evaluate ancestry-specific associations between common TPBG variants and Parkinson’s disease (PD) risk in the Global Parkinson’s Genetic Program (GP2).

Background: The trophoblastic glycoprotein (TPBG) gene encodes a leucine-rich transmembrane glycoprotein expressed in trophoblast cells and multiple adult tissues, including the brain. Knockout of its mouse orthologue Tpbg leads to PD-like phenotypes and degeneration of midbrain dopaminergic neurons, highlighting TPBG as a potential PD risk gene. However, the contribution of TPBG variants to PD risk remains unclear.

Method: TPBG variants were analysed in 44,838 PD cases and 28,722 healthy controls across 11 ancestries using NeuroBooster array (NBA) genotyping data from GP2 release 11. Variants with MAF>1% were extracted using PLINK 1.9. Association analyses were performed between PD cases and controls. Logistic regression (GLM) adjusted for age, sex, and the first five principal components was applied to coding variants. Bonferroni correction was used to account for multiple testing.

Results: Using the largest case-control PD dataset to date, and without restricting by variant type, we identified multiple variants in all ancestries. However, after Bonferroni-correction, significant variants were retained only in the Latino and Indigenous Americas populations (AMR), East Asian (EAS), and Finnish population isolate (FIN) groups. Following GLM and functional filtering, one exonic non-synonymous variant (p.(Ala118Val)) remained Bonferroni-significant in the FIN population. The variant had an alternate allele frequency of 0.015 (4/258 alleles) in 129 PD cases and 0.125 (4/36) in 18 controls, and was associated with a modest reduction in PD risk (OR=0.006, 95% CI: 0.00019-0.175, p=0.003).

Conclusion: Our findings suggest a potential association between TPBG variants and PD risk in the Finnish subset. Although the small sample size means this signal may represent a false positive and requires replication in independent cohorts. Analysis of whole genome sequencing data from GP2 may further clarify the contribution of rare and coding TPBG variants not captured by array-based genotyping. This study underscores the importance of ancestry-specific analyses and continued inclusion of diverse populations in PD genetic research.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/limited-evidence-for-tpbg-variants-in-parkinsons-disease-risk-across-global-ancestries/