Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease

Ruskey, Jennifer A.; Greenbaum, Lior; Roncière, Léanne; Alam, Armaghan; Spiegelman, Dan; Liong, Christopher; Levy, Oren; Waters, Cheryl; Fahn, Stanley; Marder, Karen; Chung, Wendy K.; Yahalom, Gilad; Israeli‐Korn, Simon; Livneh, Vered; Fay-Karmon, Tsvia; Alcalay, Roy N.; Hassin‐Baer, Sharon; Gan‐Or, Ziv

doi:10.1016/j.ejmg.2018.05.005

Cited by 51 publications

(53 citation statements)

References 17 publications

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“…Additionally, the majority of the PROBAND dataset individuals were Sanger sequenced for the full GBA gene as described elsewhere (Malek et al 2018). In the McGill dataset, GBA variants were confirmed using Sanger sequencing or targeted next generation sequencing as previously described (Ruskey et al 2019). Overall, the concordance rate between the imputed/genotype data and the sequence data for the presence of at least one p.N370S and p.T369M allele was 100% and for p.E326K was 98% and 94% in the nextgeneration and Sanger sequencing data, respectively (see Supplementary data for more details).…”

Section: Gba Variant Validationmentioning

confidence: 95%

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Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Blauwendraat

Reed

Krohn

et al. 2019

Preprint

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Parkinson's disease (PD) is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of PD, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes.Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as PD and Lewy body dementia (LBD). These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4-to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known PD risk variants.Using multiple, large case-control datasets, totalling 217,165 individuals (22,757 PD cases, 13,431 PD proxy cases, 622 LBD cases and 180,355 controls), we identified 1,772 PD cases, 711 proxy cases and 7,624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent PD-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall PD genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S neurons were shown to have decreased Cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated PD risk and age at onset and demonstrate that variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have important implications for selection of GBA carriers for therapeutic interventions. 5

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Section: Gba Variant Validationmentioning

confidence: 95%

“…For analyses, variants that passed the following post-imputation criteria were included: Sheba Medical Center, Ramat Gan, Israel (Ruskey et al 2019). Genotype quality control, processing, and analysis was performed similar to the above described genotyping data.…”

Section: Lewy Body Dementia Genotyping Datamentioning

confidence: 99%

Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Blauwendraat

Reed

Krohn

et al. 2019

Preprint

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“…The frequency of all rearrangements affecting GBA may be even higher, as they were found in 1.6% of PD patients in one study with extensive analysis of exome data (Spataro et al, ). Another recent study with a combined short‐read and Sanger approach did not report any recombinants in 735 PD patients (Ruskey et al, ), but at least one likely recombinant, RecN370S, appears to have been missed. Other large PD studies used a variety of methods and did not report recombinant alleles, which could have been missed (Jesús et al, ; Kalinderi et al, ; Winder‐Rhodes et al, ).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the detection of GBA missense mutations and other variants using the Oxford Nanopore MinION

Leija‐Salazar

Sedlazeck

Toffoli

et al. 2019

Molec Gen & Gen Med

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Background Mutations in GBA cause Gaucher disease when biallelic and are strong risk factors for Parkinson's disease when heterozygous. GBA analysis is complicated by the nearby pseudogene. We aimed to design and validate a method for sequencing GBA using long reads. Methods We sequenced GBA on the Oxford Nanopore MinION as an 8.9 kb amplicon from 102 individuals, including patients with Parkinson's and Gaucher diseases. We used NanoOK for quality metrics, NGMLR to align data (after comparing with GraphMap), Nanopolish and Sniffles to call variants, and WhatsHap for phasing. Results We detected all known missense mutations in these samples, including the common p.N409S (N370S) and p.L483P (L444P) in multiple samples, and nine rarer ones, as well as a splicing and a truncating mutation, and intronic SNPs. We demonstrated the ability to phase mutations, confirm compound heterozygosity, and assign haplotypes. We also detected two known risk variants in some Parkinson's patients. Rare false positives were easily identified and filtered, with the Nanopolish quality score adjusted for the number of reads a very robust discriminator. In two individuals carrying a recombinant allele, we were able to detect and fully define it in one carrier, where it included a 55‐base pair deletion, but not in another one, suggesting a limitation of the PCR enrichment method. Missense mutations were detected at the correct zygosity, except for the case where the RecNciI one was missed. Conclusion The Oxford Nanopore MinION can detect missense mutations and an exonic deletion in this difficult gene, with the added advantages of phasing and intronic analysis. It can be used as an efficient research tool, but additional work is required to exclude all recombinants.

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“…In most populations, 4%-12% of PD patients carry a heterozygous GBA1 variant and in Ashkenazi Jewish PD patients this is approximately 20%. 2,3 The risk of PD in GBA1 variant carriers is increased by an estimated overall 2-to 7-fold (odds ratios [ORs]). [2][3][4][5] Rare homozygous or compound heterozygous GBA1 variants can cause the autosomalrecessive lysosomal storage disorder Gaucher's disease (GD).…”

mentioning

confidence: 99%

“…2,3 The risk of PD in GBA1 variant carriers is increased by an estimated overall 2-to 7-fold (odds ratios [ORs]). [2][3][4][5] Rare homozygous or compound heterozygous GBA1 variants can cause the autosomalrecessive lysosomal storage disorder Gaucher's disease (GD). More than 400 variants have been reported to be associated with GD, 6,7 and all these alleles are potential risk factors for developing PD.…”

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confidence: 99%

A Large‐Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands

et al. 2020

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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 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 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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Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease

Abstract: Without full sequencing of GBA, or at minimum including p.E326K in the genotyping panel, a significant proportion of variant carriers go undiscovered and may be incorrectly assigned as non-carriers in studies or clinical trials.

Cited by 51 publications

References 17 publications

Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Evaluation of the detection of GBA missense mutations and other variants using the Oxford Nanopore MinION

A Large‐Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands

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