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Neurosci Lett. 2017 Sep 29;658:48-52. doi: 10.1016/j.neulet.2017.08.040. Epub 2017 Aug 19.

The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal.

Author information

1
Department of Neurology, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: berge.victoria@gmail.com.
2
Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: lasse.pihlstrom@gmail.com.
3
The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway; The Centre for Organelle Research, University of Stavanger, Stavanger, Norway. Electronic address: jodi.maple.grodem@sus.no.
4
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden. Electronic address: lars.forsgren@umu.se.
5
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden. Electronic address: jan.linder@umu.se.
6
Network for Medical Sciences, University of Stavanger, Stavanger, Norway. Electronic address: nevrologlarsen@gmail.com.
7
Department of Neurology, Haukeland University Hospital, Bergen, Norway. Electronic address: ole-bjorn.tysnes@helse-bergen.no.
8
Department of Neurology, Oslo University Hospital, Oslo, Norway. Electronic address: mathias.toft@gmail.com.

Abstract

OBJECTIVE:

Coding variants in the GBA gene have been identified as the numerically most important genetic risk factors for Parkinson's disease (PD). In addition, genome-wide association studies (GWAS) have identified associations with PD in the SYT11-GBA region on chromosome 1q22, but the relationship to GBA coding variants have remained unclear. The aim of this study was to sequence the complete GBA gene in a clinical cohort and to investigate whether coding variants within the GBA gene may be driving reported association signals.

METHODS:

We analyzed high-throughput sequencing data of all coding exons of GBA in 366 patients with PD. The identified low-frequency coding variants were genotyped in three Scandinavian case-controls series (786 patients and 713 controls). Previously reported risk variants from two independent association signals within the SYT11-GBA locus on chromosome 1 were also genotyped in the same samples. We performed association analyses and evaluated linkage disequilibrium (LD) between the variants.

RESULTS:

We identified six rare mutations (1.6%) and two low-frequency coding variants in GBA. E326K (rs2230288) was significantly more frequent in PD patients compared to controls (OR 1.65, p=0.03). There was no clear association of T369M (rs75548401) with disease (OR 1.43, p=0.24). Genotyping the two GWAS hits rs35749011 and rs114138760 in the same sample set, we replicated the association between rs35749011 and disease status (OR 1.67, p=0.03), while rs114138760 was found to have similar allele frequencies in patients and controls. Analyses revealed that E326K and rs35749011 are in very high LD (r2 0.95).

CONCLUSIONS:

Our results confirm that the GBA variant E326K is a susceptibility allele for PD. The results suggest that E326K may fully account for the primary association signal observed at chromosome 1q22 in previous GWAS of PD.

KEYWORDS:

E326K; GWAS; Glucocerebrosidase; Parkinson’s disease; Synaptotagmin 11; T369M

PMID:
28830825
DOI:
10.1016/j.neulet.2017.08.040
[Indexed for MEDLINE]

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