Objective: To studied a previously proposed polygenic risk scores (PRSs) for PD selected for the LRRK2 gene in a genetic data set of Russian population with following association analysis of PRSs with lysosomal hydrolase activity.

Background: Parkinson’s disease (PD) is a multifactorial progressive neurodegenerative disorder. Previously, we showed the association of exonic variants of the LRRK2 gene on the activity of lysosomal hydrolases in PD patients suggested that LRRK2 dysfunction may impair sphingolipid metabolism in PD [1]. Polygenic risk scores (PRSs) are one way to aggregate the effects of a large number of genetic variants upon the disease and in particularly, upon PD risk [2]. It is unknown whether the cumulative effect of the LRRK2 gene variants influences the risk of PD and sphingolipid metabolism.

Method: 508 PD cases and 478 controls of the Russian origin were included in the current study. Full screening of the LRRK2 gene was conducted. Quality control was performed with PLINK 1.9. and also, was carried out with thresholds of 0.01 for the minor allele frequency for SNPs. We evaluated PRS of the LRRK2 gene for PD (PD-PRS-LRRK2) from the full list of the 1805 SNPs published earlier by Nalls and coauthors [2]. Logistic regression analysis was performed treating the case-control status as outcome and the PD-PRS-LRRK2 value as influence variable, adjusted for sex and age. Activity of lysosomal enzymes (glucocerebrosidase (GCase), alpha-galactosidase A (GLA), acid sphingomyelinase (ASMase) and substrate concentrations (hexosylsphingosine (HexSph), globotriaosylsphingosine (LysoGb3), lysosphingomyelin (LysoSM), respectively) were estimated in blood by LC-MS-MS.

Results: Individuals with PRS-PD-LRRK2 had an about 2.23-fold higher risk of PD (OR=2.23, 95%CI: 1.28-4.23, p=0.005). As well, PRS-PD-LRRK2 was increased in PD patients compared to controls (p=0.011). Additionally, we estimated association of PRS-PD-LRRK2 with lysosomal hydrolase activity and lysosphingolipid concentrations. Association between LysoSM concentration and PRS-PD-LRRK2 in PD patients and in PD patients with controls together was found (b=1.1300 , p=0.00142; b= 1.0947, p=0.00027, respectively).

Conclusion: Variants of the LRRK2 contribute to the risk of PD including cumulative risk and associated with alteration of sphingolipid metabolism.

References: 1.Usenko TS, Senkevich KA, Basharova KS, Bezrukova AI et al., LRRK2 exonic variants are associated with lysosomal hydrolase activities and lysosphingolipid alterations in Parkinson’s disease. Gene. 2023. 882:147639. doi: 10.1016/j.gene.2023.147639
2. Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K et al.. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2019. 8(12):1091-1102. doi: 10.1016/S1474-4422(19)30320-5

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-of-polygenic-risk-score-of-the-lrrk2-gene-for-parkinsons-disease-with-lysosomal-hydrolase-activities-in-the-russian-population-based-on-genetic-profile-and-established-risk-factor/