Multi-center analysis of glucocerebrosidase mutations in Parkinson disease

By E. Sidransky, M. Nalls, J. Aasly, Judith Aharon-Peretz, G. Annesi, E. Barbosa, A. Bar-Shira, D. Berg, J. Bras, A. Brice and 52 more. New England Journal of Medicine, 2009

1,060 citations recorded by the source corpus.

Background Recent studies indicate an increased frequency of mutations in the gene for Gaucher disease, glucocerebrosidase (GBA), among patients with Parkinson disease. An international collaborative study was conducted to ascertain the frequency of GBA mutations in ethnically diverse patients with Parkinson disease. Methods Sixteen centers participated, including five from the Americas, six from Europe, two from Israel and three from Asia. Each received a standard DNA panel to compare genotyping results. Genotypes and phenotypic data from patients and controls were analyzed using multivariate logistic regression models and the Mantel Haenszel procedure to estimate odds ratios (ORs) across studies. The sample included 5691 patients (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews). Results All 16 centers could detect GBA mutations, L444P and N370S, and the two were found in 15.3% of Ashkenazi patients with Parkinson disease (ORs = 4.95 for L444P and 5.62 for N370S), and in 3.2% of non-Ashkenazi patients (ORs = 9.68 for L444P and 3.30 for N370S). GBA was sequenced in 1642 non-Ashkenazi subjects, yielding a frequency of 6.9% for all mutations, demonstrate that limited mutation screens miss half the mutant alleles. The presence of any GBA mutation was associated with an OR of 5.43 across studies. Clinically, although phenotypes varied, subjects with a GBA mutation presented earlier, and were more likely to have affected relatives and atypical manifestations. Conclusion Data collected from sixteen centers demonstrate that there is a strong association between GBA mutations and Parkinson disease.

Subfields: Epidemiology, Physiology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/09a3a4af20b5a6648eb463e9cf2f5d13d4e211e3

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In Epidemiology

1. Andrea Ballabio
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1. G. Napolitano
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Citations in the corpus

• Gaucher’s Disease Glucocerebrosidase and -synuclein form a bidirectional pathogenic loop in synucleinopathies (2011, positive): “Importantly, several additional genetic studies in large patient cohorts demonstrated that patients with parkinsonism have an increased incidence of GBA1mutations (Lill et al., 2008; Sidransky et al., 2009), makingGBA1 the most common known genetic risk factor for PD to date.”
• TFEB at a glance (2016, background): “Remarkably, heterozygous mutations in the gene encoding for the lysosomal enzyme glucocerebrosidase have been found in a substantial number of patients with Parkinson’s disease (Sidransky et al., 2009), further supporting a role for lysosomal dysfunction in the pathogenesis of the disorder.”
• Epidemiology and etiology of Parkinson’s disease: a review of the evidence (2011, neutral): “[267].”