Strong association between glucocerebrosidase mutations and Parkinson's disease in Sweden

Abstract

Several genetic studies have demonstrated an association between mutations in glucocerebrosidase (GBA), originally implicated in Gaucher's disease, and an increased risk of Parkinson's disease (PD). We have investigated the possible involvement of genetic GBA variations in PD in the Swedish population. Three GBA variants, E326K, N370S, and L444P were screened in the largest Swedish Parkinson cohort reported to date; 1625 cases and 2025 control individuals. We found a significant association with high effect size of the rare variant L444P with PD (odds ratio 8.17; 95% confidence interval: 2.51–26.23; p-value = 0.0020) and a significant association of the common variant E326K (odds ratio 1.60; 95% confidence interval: 1.16–2.22; p-value = 0.026). The rare variant N370S showed a trend for association. Most L444P carriers (68%) were found to reside in northern Sweden, which is consistent with a higher prevalence of Gaucher's disease in this part of the country. Our findings support the role of GBA mutations as risk factors for PD and point to lysosomal dysfunction as a mechanism contributing to PD etiology.

Genetic risk factors in Finnish patients with Parkinson's disease

“…The allele frequency of the two mutations is high among Ashkenazi Jewish PD patients with a total frequency of 15.3%. The combined frequency of the two mutations is approximately 3.2% in non-Ashkenazi Jewish PD patients [8], 2.3% in Norwegian patients [8] and 2.8% in Swedish patients [19], whereas among non-Finnish Europeans in the ExAC database the frequency is 0.8%. We found these GBA mutations in 2.8% of the EOPD patients giving a relative risk of 3.8 for PD and in 1.9% of the LOPD patients giving a relative risk of 2.5.…”

The clinical features of Parkinson’s disease in patients with mutations and polymorphic variants of GBA gene

“…Нами проведено исследование особенностей клинического течения у пациентов с мутациями (N370S, L444P) и полиморфными вариантами (E326K, T369M) гена GBA. Показано, что частота БП, ассоциированная с наличием скринируемых генетических вариантов гена GBA, соответствует данным, полученным в европейских популяци-ях [21,22]. Более раннее начало заболевания по сравнению со сБП было выявлено у пациентов с мутациями, но не с полиморфными вариантами гена GBA, что соответствует полученным ранее результатам [13].…”

Concise Review: Induced Pluripotent Stem Cell Research in the Era of Precision Medicine

“…It has been recently shown that especially rare genetic variants, such as homozygous variant defects resulting in rare pathologies, can associate for increased risk of more common maladies as well. For example, having a pathogenic GBA mutation for Gaucher's Disease (GD) (e.g., N370S, L444P) in one allele (carrier) will not usually manifest the full symptoms of GD, but does increase risk for Parkinson's disease . The odds ratio for the GBA mutation in PD was greater than 5, which is unusually high compared to risk loci found from GWAS .…”