GBA mutations p.N370S and p.L444P are associated with Parkinson's disease in patients from Northern Brazil

Amaral, Carlos Eduardo de Melo; Lopes, Patrick Farias; Ferreira, Juliana Cristina Cardoso; Alves, Erik Artur Cortinhas; Montenegro, Marcella Vieira Barroso; Costa, Everardo Andrade da; Yamada, Elizabeth Sumi; Cavalcante, Fernando Otávio Quaresma; Silva, Luiz Carlos Santana da

doi:10.1590/0004-282x20190006

Cited by 11 publications

(13 citation statements)

References 31 publications

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“…The Amaral et al 3 study further reinforces the association of mutations of the GBA gene as a factor of genetic susceptibility for the development of PD in the Brazilian population.…”

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confidence: 61%

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GBA mutations and Parkinson's disease in Brazil

Rieder

2019

Arq. Neuro-Psiquiatr.

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“…The Amaral et al 3 study further reinforces the association of mutations of the GBA gene as a factor of genetic susceptibility for the development of PD in the Brazilian population.…”

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confidence: 61%

“…In the Amaral et al 3 study, all six PD patients with one of the mutations presented clinically as a typical PD phenotype. The authors found that patients with p.L444P mutation showed a tendency to present with earlier disease onset.…”

mentioning

confidence: 96%

GBA mutations and Parkinson's disease in Brazil

Rieder

2019

Arq. Neuro-Psiquiatr.

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“…Researchers worldwide have attempted to validate the same association in populations from many different genetic backgrounds [31][32][33][34][35][36][37][38][39][40][41]. In 2009, an international and multicenter study with a great sample of approximately 5000 PD patients and equal number of controls provided the definitive proof found for this association with an odds ratio greater than five (OR 5.3) and showed that mutations N370S and L444P are the most frequent in this gene.…”

Section: Gba: the Principal Genetic Risk Factor For Parkinson Diseasementioning

confidence: 98%

“…Whether in heterozygosis or in homozygosis individuals (GD patients), the age of onset of symptoms apparently occurs earlier than in PD patients without mutations, usually between the fourth and sixth decade of life [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]. In relation to symptoms is noticeable a cognitive decline earlier in PD patients with GBA mutations (PD-GBA) [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Dementia is one of the clinical manifestations that most affects the patient's quality of life and it is more frequent in GBA mutation carriers than in non-carriers.…”

Section: Gba: the Principal Genetic Risk Factor For Parkinson Diseasementioning

confidence: 99%

Genetic Risk Factors and Lysosomal Function in Parkinson Disease

Montenegro¹,

Amaral²,

Silva³

2021

Methods in Molecular Medicine

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Parkinson disease is a complex disease that has multiple genetic and environmental factors. To achieve the early diagnosis and to be able to modify the disease progression, efforts are being made to identify individuals at risk. About 20 year ago, an evidence of major prevalence of Parkinsonism in patients with Gaucher Disease reported by studies worldwide led to the putative involvement of the GBA gene. Nowadays, the link from a rare disease with a common disease is well known and it is confirmed that mutations in the GBA gene are the most important genetic risk factor. Apart from rare mutations, genetic association studied appointed common variants in genes well associated with familial cases as LRRK2 and SNCA may also contribute to the increased risk for sporadic cases. Other common variants in the MAPT gene were also reported. At least, genetic studies have been observed an excessive burden of relevant variants in genes with lysosomal function. Thus, a synergistic action of variants in genes that codifies proteins involved with the lysosome may be a mean of modulating the risk. In this chapter, we review the most robust genetic risk factor and the relevance of lysosomal function for Parkinson disease.

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“…Even if not located on a specific common allele, rare variants in GWAS genes may contribute to disease. For example, rare variants in SNCA (Polymeropoulos et al, 1997), GBA (Sidransky et al, 2009;Ran et al, 2016;Emelyanov et al, 2018;Amaral et al, 2019), LRRK2 (Paisan-Ruiz et al, 2004;Khan et al, 2005), VPS13C (Lesage et al, 2016;Jansen et al, 2017;Darvish et al, 2018;Schormair et al, 2018;Rudakou et al, 2020), GCH1 (Mencacci et al, 2014;Guella et al, 2015;Lewthwaite et al, 2015;Xu et al, 2017;Yoshino et al, 2018;Rudakou et al, 2019), all GWAS loci genes, also cause or increase the risk of Parkinson's disease.…”

Section: Introductionmentioning

confidence: 99%

Targeted sequencing of Parkinson’s disease loci genes highlightsSYT11, FGF20and other associations

Rudakou

Krohn

et al. 2020

Preprint

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Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2,657 patients and 3,647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests (SKAT-O). The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (p=5.23E-05 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5′ UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's Disease is driven by rare nonsynonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in ten and eight controls, respectively, but not in patients. We ideniified common variants associated with Parkinson′s disease in MAPT, TMEM175, BST1, SNCA and GPNMB which are all in strong linkage disequilibrium (LD) with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (OR 0.73, 95% CI 0.60-0.89, p=1.161E-03). This variant is not in LD with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.

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GBA mutations p.N370S and p.L444P are associated with Parkinson's disease in patients from Northern Brazil

Cited by 11 publications

References 31 publications

GBA mutations and Parkinson's disease in Brazil

GBA mutations and Parkinson's disease in Brazil

Genetic Risk Factors and Lysosomal Function in Parkinson Disease

Targeted sequencing of Parkinson’s disease loci genes highlightsSYT11, FGF20and other associations

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