Background: The most common genetic risk factor for Parkinson’s disease known is a damaging variant in the GBA1 gene. The entire GBA1 gene has rarely been studied in a large cohort from a single population. The objective of this study was to assess the entire GBA1 gene in Parkinson’s disease from a single large population. Methods: The GBA1 gene was assessed in 3402 Dutch Parkinson’s disease patients using nextgeneration sequencing. Frequencies were compared with Dutch controls (n = 655). Family history of Parkinson’s disease was compared in carriers and noncarriers. Results: Fifteen percent of patients had a GBA1 nonsynonymous variant (including missense, frameshift, and recombinant alleles), compared with 6.4% of controls (OR, 2.6; P < 0.001). Eighteen novel variants were detected. Variants previously associated with Gaucher’s disease were identified in 5.0% of patients compared with 1.5% of controls (OR, 3.4; P < 0.001). The rarely reported complex allele p.D140H + p.E326K appears to likely be a Dutch founder variant, found in 2.4% of patients and 0.9% of controls (OR, 2.7; P = 0.012). The number of first-degree relatives (excluding children) with Parkinson’s disease was higher in p.D140H + p.E326K carriers (5.6%, 21 of 376) compared with p.E326K carriers (2.9%, 29 of 1014); OR, 2.0; P = 0.022, suggestive of a dose effect for different GBA1 variants. Conclusions: Dutch Parkinson’s disease patients display one of the largest frequencies of GBA1 variants reported so far, consisting in large part of the mild p.E326K variant and the more severe Dutch p.D140H + p.E326K founder allele. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Keywords familial aggregation, GBA sequencing, genetic risk factor, glucocerebrosidase, heredity
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Journal Movement Disorders
den Heijer, J.M., Cullen, V.C., Quadri, M, Schmitz, A, Hilt, D.C., Lansbury, P., … Groeneveld, G.J. (2020). A Large-Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands. Movement Disorders, 35(9), 1667–1674. doi:10.1002/mds.28112