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The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal
Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
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2017 (engelsk)Inngår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 658, s. 48-52Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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 (r(2) 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.

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Elsevier, 2017. Vol. 658, s. 48-52
Emneord [en]
Parkinson's disease, Glucocerebrosidase, E326K, T369M, Synaptotagmin 11, GWAS
HSV kategori
Identifikatorer
URN: urn:nbn:se:umu:diva-141999DOI: 10.1016/j.neulet.2017.08.040ISI: 000414115200009PubMedID: 28830825OAI: oai:DiVA.org:umu-141999DiVA, id: diva2:1159020
Tilgjengelig fra: 2017-11-21 Laget: 2017-11-21 Sist oppdatert: 2018-06-09bibliografisk kontrollert

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