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Heijer, J.M. den; 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

Article / Letter to editor
Background The most common genetic risk factor for Parkinson's disease known is a damaging variant in theGBA1gene. The entireGBA1gene has rarely been studied in a large cohort from a single population. The objective of this study was to assess the entireGBA1gene in Parkinson's disease from a single large population. Methods TheGBA1gene was assessed in 3402 Dutch Parkinson's disease patients using next-generation 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 aGBA1nonsynonymous 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...Show moreBackground The most common genetic risk factor for Parkinson's disease known is a damaging variant in theGBA1gene. The entireGBA1gene has rarely been studied in a large cohort from a single population. The objective of this study was to assess the entireGBA1gene in Parkinson's disease from a single large population. Methods TheGBA1gene was assessed in 3402 Dutch Parkinson's disease patients using next-generation 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 aGBA1nonsynonymous 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 differentGBA1variants. Conclusions Dutch Parkinson's disease patients display one of the largest frequencies ofGBA1variants reported so far, consisting in large part of the mild p.E326K variant and the more severe Dutch p.D140H + p.E326K founder allele. (c) 2020 International Parkinson and Movement Disorder SocietyShow less
familial aggregation
GBA sequencing
genetic risk factor
glucocerebrosidase
heredity
All authors
Heijer, J.M. den; Cullen, V.C.; Quadri, M.; Schmitz, A.; Hilt, D.C.; Lansbury, P.; Berendse, H.W.; Berg, W.D.J. van de; Bie, R.M.A. de; Boertien, J.M.; Boon, A.J.W.; Contarino, M.F.; Hilten, J.J. van; Hoff, J.I.; Mierlo, T. van; Munts, A.G.; Plas, A.A. van der; Ponsen, M.M.; Baas, F.; Majoor-Krakauer, D.; Bonifati, V.; Laar, T. van; Groeneveld, G.J.
Date
2020-07-02
Journal
Movement Disorders
Volume
35
Issue
9
Pages
1667 - 1674
DOI
doi:10.1002/mds.28112
Link
https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.28112