Lack of association between G6PD variants and Parkinson disease

Oxidative stress has been implicated in Parkinson disease (PD). Genes involved in PD, such as PRKN, PINK1, and PARK7, contribute to oxidative stress in dopaminergic neurons. The X-linked G6PD gene encodes glucose 6-phosphate dehydrogenase, an important regulator of oxidative stress. Recent studies suggested that alpha-synuclein aggregates may impair G6PD activity and contribute to dopaminergic neuron loss, and that G6PD mutations may independently increase the risk of PD. In this study, we aimed to examine the role of common and rare G6PD variants in PD across 6 cohorts, including 8,905 PD cases, 16,770 proxy cases, and 394,098 controls. These cohorts were analyzed after stratification by sex and then combined to account for the G6PD X-linked location. Using logistic regression, we did not identify significant associations for common variants in any of the cohorts. The optimized sequence Kernel association (SKAT-O) test was performed to assess the effect of rare variants (minor allele frequency <0.01) across six cohorts, followed by a meta-analysis using metaSKAT, also demonstrating lack of association. In conclusion, we did not find evidence for a role for G6PD in PD.

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Publication Details

Journal
Human Genetics and Genomics Advances
Published
2025-12-10
DOI
https://doi.org/10.1016/j.xhgg.2025.100555
Primary Topic
Neonatal Health and Biochemistry
Type
article
Field-Weighted Citation Impact
0.00
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article

Lack of association between G6PD variants and Parkinson disease

Konstantin A. Senkevich, Farnaz Asayesh, Cheryl Waters, Leonard L. Sokol et al.
Human Genetics and Genomics Advances
Neonatal Health and Biochemistry
article

Lack of association between G6PD variants and Parkinson disease

Konstantin A. Senkevich, Farnaz Asayesh, Cheryl Waters, Leonard L. Sokol, Jennifer A. Ruskey, Oury Monchi, Sharon Hassin‐Baer, Roy N. Alcalay, Alberto J. Espay, Sitki Cem Parlar, Irina Miliukhina, Lang Liu, Dan Spiegelman, Lior Greenbaum, Nicolas Dupré, Yves A Dauvilliers, Ziv Gan‐Or, Jamil Ahmad, Eric Yu, Alla Timofeeva, Anton Emelyanov, Sofya Pchelina, Leah V. Chifamba
article en

Abstract

Oxidative stress has been implicated in Parkinson disease (PD). Genes involved in PD, such as PRKN, PINK1, and PARK7, contribute to oxidative stress in dopaminergic neurons. The X-linked G6PD gene encodes glucose 6-phosphate dehydrogenase, an important regulator of oxidative stress. Recent studies suggested that alpha-synuclein aggregates may impair G6PD activity and contribute to dopaminergic neuron loss, and that G6PD mutations may independently increase the risk of PD. In this study, we aimed to examine the role of common and rare G6PD variants in PD across 6 cohorts, including 8,905 PD cases, 16,770 proxy cases, and 394,098 controls. These cohorts were analyzed after stratification by sex and then combined to account for the G6PD X-linked location. Using logistic regression, we did not identify significant associations for common variants in any of the cohorts. The optimized sequence Kernel association (SKAT-O) test was performed to assess the effect of rare variants (minor allele frequency <0.01) across six cohorts, followed by a meta-analysis using metaSKAT, also demonstrating lack of association. In conclusion, we did not find evidence for a role for G6PD in PD.

Human Genetics and Genomics AdvancesVol. 7(1)
Scripps Research Institute (US), Montreal Neurological Institute and Hospital (CA), Scripps Health (US), Columbia University Irving Medical Center (US), First Pavlov State Medical University of St. Petersburg (RU), Tel Aviv Sourasky Medical Center (IL), Sheba Medical Center (IL), McGill University Health Centre (CA), Centre Hospitalier Universitaire de Montpellier (FR), Institute of the Human Brain (RU), Hôpital Gui de Chauliac (FR), Institut Universitaire de Gériatrie de Montréal (CA), Scripps Clinic (US), Université Laval (CA), McGill University (CA), University of Cincinnati (US)
Openalex Percentile: Top 51%
Neonatal Health and Biochemistry
DOIOpen Access PDFOpenAlex
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