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The GBA variant E32...
The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal
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Berge-Seidl, Victoria (författare)
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Pihlstrøm, Lasse (författare)
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Maple-Grødem, Jodi (författare)
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- Forsgren, Lars (författare)
- Umeå universitet,Klinisk neurovetenskap
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- Linder, Jan (författare)
- Umeå universitet,Klinisk neurovetenskap
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Larsen, Jan Petter (författare)
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Tysnes, Ole-Bjørn (författare)
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Toft, Mathias (författare)
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(creator_code:org_t)
- Elsevier, 2017
- 2017
- Engelska.
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Ingår i: Neuroscience Letters. - : Elsevier. - 0304-3940 .- 1872-7972. ; 658, s. 48-52
- Relaterad länk:
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https://www.duo.uio....
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
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- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Nyckelord
- Parkinson's disease
- Glucocerebrosidase
- E326K
- T369M
- Synaptotagmin 11
- GWAS
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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