Objective: To investigate the association between PGLYRP2 polymorphisms and Parkinson’s disease (PD) across diverse ancestral populations.

Background: Emerging evidence suggests a role of the gastrointestinal (GI) system in PD pathogenesis [1]. Single nucleotide polymorphisms (SNPs) in peptidoglycan recognition proteins (PGRPs) genes, essential for gut immune homeostasis, have been linked to PD [2]. In particular, PGLYRP2 variants, including the SNP rs892145, have been associated with PD, with reported sex differences in effect sizes [3].

Method: Data from the Global Parkinson’s Genetics Program (GP2, https://gp2.org/) was leveraged, analyzing 22,166 PD cases and 14,306 controls, across ten ancestral groups. PGLYRP2 (GRCh38) genomic region was extracted, and all identified variants were assessed and annotated using ANNOVAR. Burden analyses included coding and rare (MAF <3%) SNPs. Individual variant-phenotype associations were tested, adjusting for sex and the first five genetic principal components. A formal interaction test between rs892145 and sex was conducted, followed by a sex-stratified analysis.

Results: Several variants showed nominal significance in allele frequency comparisons between cases and controls but were lost after Bonferroni correction. The association between rs892145 and PD was examined separately, observing a trend in the African (AFR) ancestry (OR: 0.89, CI95: 0.78 – 1.0, p = 0.057). The interaction test identified a significant sex-dependent effect in males in this same ancestry group (OR: 0.7, CI95: 0.60-0.98, p<0.05). The subsequent sex-stratified analysis revealed a protective effect in males from the AFR (OR: 0.78, CI95: 0.66-0.91) and Latino and Indigenous people of the Americas (AMR) (OR: 0.62, CI95: 0.42-0.91) populations [Figure 1]. Gene-based burden analysis demonstrated significant associations (p<0.05) between the aggregation of coding and rare variants in the AAC, AMR and AFR ancestry groups.

Conclusion: Our findings suggest that rs892145 may have a protective effect in PD in male AFR and AMR carriers, highlighting a potential sex-dependent role of this SNP in the pathophysiology of the disease within specific ancestries. Moreover, these results align with prior evidence but challenge previous reports suggesting different effect directions [3]. Further studies in diverse populations with larger sample sizes are needed to clarify these associations.

Fig 1. Forest plot of rs892145 association with PD

References: [1] Salim S, Ahmad F, Banu A, Mohammad F. Gut microbiome and Parkinson’s disease: Perspective on pathogenesis and treatment. J Adv Res 2023;50:83–105. https://doi.org/10.1016/j.jare.2022.10.013.

[2] Goldman SM, Kamel F, Ross GW, Jewell SA, Marras C, Hoppin JA, et al. Peptidoglycan recognition protein genes and risk of Parkinson’s disease. Mov Disord 2014;29:1171–80. https://doi.org/10.1002/mds.25895.

[3] Ran C, Wirdefeldt K, Sydow O, Svenningsson P, Diaz Heijtz R. Sex Differences in the Allele Distribution of PGLYRP2 Variant rs892145 in Parkinson’s Disease. Parkinsons Dis 2023;2023:6502727. https://doi.org/10.1155/2023/6502727.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sex-dependent-associations-between-pglyrp2-variants-and-parkinsons-disease-across-diverse-ancestries/