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. 2023 May;38(5):899-903.
doi: 10.1002/mds.29342. Epub 2023 Mar 3.

Polygenic Parkinson's Disease Genetic Risk Score as Risk Modifier of Parkinsonism in Gaucher Disease

Cornelis Blauwendraat  1   2 , Nahid Tayebi  3 , Elizabeth Geena Woo  3 , Grisel Lopez  3 , Luca Fierro  4 , Marco Toffoli  5 , Naomi Limbachiya  5 , Derralynn Hughes  6 , Vanessa Pitz  1 , Dhairya Patel  1 , Dan Vitale  2   7 , Mathew J Koretsky  2 , Dena Hernandez  8 , Raquel Real  5 , Roy N Alcalay  9   10 , Mike A Nalls  2   7   8 , Huw R Morris  5 , Anthony H V Schapira  5 , Manisha Balwani  4 , Ellen Sidransky  3
Affiliations

Polygenic Parkinson's Disease Genetic Risk Score as Risk Modifier of Parkinsonism in Gaucher Disease

Cornelis Blauwendraat et al. Mov Disord. 2023 May.

Abstract

Background: Biallelic pathogenic variants in GBA1 are the cause of Gaucher disease (GD) type 1 (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. Heterozygous GBA1 variants are also a common genetic risk factor for Parkinson's disease (PD). GD manifests with considerable clinical heterogeneity and is also associated with an increased risk for PD.

Objective: The objective of this study was to investigate the contribution of PD risk variants to risk for PD in patients with GD1.

Methods: We studied 225 patients with GD1, including 199 without PD and 26 with PD. All cases were genotyped, and the genetic data were imputed using common pipelines.

Results: On average, patients with GD1 with PD have a significantly higher PD genetic risk score than those without PD (P = 0.021).

Conclusions: Our results indicate that variants included in the PD genetic risk score were more frequent in patients with GD1 who developed PD, suggesting that common risk variants may affect underlying biological pathways. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Keywords: GBA1; Gaucher; Parkinson's; genetics.

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Conflict of interest statement

Relevant conflicts of interest/financial disclosures: M.A.N. and D.V. are consultants employed by Data Tecnica International, whose participation in this is part of a consulting agreement between the US National Institutes of Health and said company.

Figures

Figure 1:
Figure 1:. Parkinson’s disease (PD) genetic risk score comparisons across cohorts and ancestries.
A) Violin plots of genetic risk score of European (EUR) ancestry control, Gaucher disease type 1 (GD1) without PD, GD1 with PD and PD cases show a higher risk score (normalized Z-score) in both GD1+PD and PD vs control and GD1 respectively. B) Identical plots for subjects with Ashkenazi Jewish (AJ) ancestry. C) Forest plot of PD - control risk score analysis of EUR and AJ ancestries shows a significant effect. D) Forest plot of GD1 without PD - GD1+PD risk score analysis of EUR and AJ ancestries shows a significant effect. Bracket end lines denote 95% CIs of the study specific estimates, with squares for effect estimates (odds ratios), and the size of these squares is proportionate to sample size. The red diamonds denote effect and 95% CI of the meta-analyzed results on the odds ratio scale.
See this image and copyright information in PMC

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