Accurate long-read sequencing identified GBA1 as major risk factor in the Luxembourgish Parkinson's study

被引：14

作者：

Pachchek, Sinthuja ^{[1
]}

Landoulsi, Zied ^{[1
]}

Pavelka, Lukas ^{[2
,3
]}

Schulte, Claudia ^{[4
]}

Buena-Atienza, Elena ^{[5
,6
]}

Gross, Caspar ^{[5
,6
]}

Hauser, Ann-Kathrin ^{[4
]}

Reddy Bobbili, Dheeraj ^{[1
]}

Casadei, Nicolas ^{[5
,6
]}

May, Patrick ^{[1
]}

Kruger, Rejko ^{[1
,2
,3
,7
,8
]}

Acharya, Geeta ^{[7
]}

Aguayo, Gloria ^{[7
]}

Alexandre, Myriam ^{[7
]}

Ali, Muhammad ^{[1
]}

Ammerlann, Wim ^{[7
]}

Arena, Giuseppe ^{[1
]}

Balling, Rudi ^{[1
]}

Bassis, Michele ^{[1
]}

Batutu, Roxane ^{[8
]}

Beaumont, Katy ^{[7
]}

Becker, Regina ^{[1
]}

Bellora, Camille ^{[7
]}

Berchem, Guy ^{[8
]}

Berg, Daniela ^{[9
,10
]}

Bisdorff, Alexandre ^{[11
]}

Boussaad, Ibrahim ^{[1
]}

Bouvier, David ^{[12
]}

Brockmann, Kathrin ^{[9
,10
]}

Calmes, Jessica ^{[7
]}

Castillo, Lorieza ^{[7
]}

Contesotto, Gessica ^{[7
]}

De Bremaeker, Nancy ^{[8
]}

Diederich, Nico ^{[8
]}

Dondelinger, Rene ^{[11
]}

E. Ramia, Nancy ^{[1
]}

Esteves, Daniela ^{[7
]}

Fagherazzi, Guy ^{[7
]}

Ferrand, Jean-Yves ^{[7
]}

Frauenknecht, Katrin ^{[12
]}

Gantenbein, Manon ^{[7
]}

Gasser, Thomas ^{[9
,10
]}

Gawron, Piotr ^{[1
]}

Ghosh, Soumyabrata ^{[1
]}

Giraitis, Marijus ^{[7
,8
]}

Glaab, Enrico ^{[1
]}

Goergen, Martine ^{[8
]}

Gomez De Lope, Elisa ^{[1
]}

Graas, Jerome ^{[7
]}

Graziano, Mariella ^{[13
]}

机构：

[1] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Esch Sur Alzette, Luxembourg

[2] Ctr Hosp Luxembourg CHL, Parkinson Res Clin, Luxembourg, Luxembourg

[3] Luxembourg Inst Hlth LIH, Transversal Translat Med, Strassen, Luxembourg

[4] Univ Tubingen, German Ctr Neurodegenerat Dis, Hertie Inst Clin Brain Res, Dept Neurodegenerat,Ctr Neurol, Tubingen, Germany

[5] Univ Tubingen, Inst Med Genet & Appl Genom, Tubingen, Germany

[6] Univ Tubingen, NGS Competence Ctr Tubingen NCCT, Tubingen, Germany

[7] Luxembourg Inst Hlth, Strassen, Luxembourg

[8] Ctr Hosp Luxembourg, Strassen, Luxembourg

[9] Univ Hosp Tubingen, Ctr Neurol, Tubingen, Germany

[10] Univ Hosp Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany

[11] Ctr Hosp Emile Mayrisch, Esch Sur Alzette, Luxembourg

[12] Lab Natl Sante, Dudelange, Luxembourg

[13] Assoc Physiotherapists Parkinsons Dis Europe, Esch Sur Alzette, Luxembourg

[14] Univ Luxembourg, Fac Sci Technol & Med, Esch Sur Alzette, Luxembourg

[15] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Epidemiol, Med Ctr, Maastricht, Netherlands

[16] Ctr Hosp Nord, Ettelbruck, Luxembourg

[17] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford Parkinsons Dis Ctr, Oxford, England

[18] Parkinson Luxembourg Assoc, Leudelange, Luxembourg

[19] Westpfalz Klinikum GmbH, Kaiserslautern, Germany

[20] Univ Oxford, Dept Psychiat, Oxford Ctr Human Brain Act, Wellcome Ctr Integrat Neuroimaging, Oxford, England

[21] Univ Med Ctr Schleswig Holstein, Dept Neurol, Kiel, Germany

[22] Ruhr Univ Bochum, Bochum, Germany

[23] Paracelsus Elena Klin, Kassel, Germany

[24] Univ Oxford, Dept Physiol Anat & Genet, Oxford Parkinsons Dis Ctr, South Parks Rd, Oxford, England

来源：

NPJ PARKINSONS DISEASE | 2023年 / 9卷 / 01期

关键词：

GLUCOCEREBROSIDASE GENE; DISEASE; MUTATIONS; E326K; ASSOCIATION; POLYMORPHISM; PROGRESSION; VARIANTS;

D O I：

10.1038/s41531-023-00595-w

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Heterozygous variants in the glucocerebrosidase GBA1 gene are an increasingly recognized risk factor for Parkinson's disease (PD). Due to the GBAP1 pseudogene, which shares 96% sequence homology with the GBA1 coding region, accurate variant calling by array-based or short-read sequencing methods remains a major challenge in understanding the genetic landscape of GBA1-associated PD. We analyzed 660 patients with PD, 100 patients with Parkinsonism and 808 healthy controls from the Luxembourg Parkinson's study, sequenced using amplicon-based long-read DNA sequencing technology. We found that 12.1% (77/637) of PD patients carried GBA1 variants, with 10.5% (67/637) of them carrying known pathogenic variants (including severe, mild, risk variants). In comparison, 5% (34/675) of the healthy controls carried GBA1 variants, and among them, 4.3% (29/675) were identified as pathogenic variant carriers. We found four GBA1 variants in patients with atypical parkinsonism. Pathogenic GBA1 variants were 2.6-fold more frequently observed in PD patients compared to controls (OR = 2.6; CI = [1.6,4.1]). Three novel variants of unknown significance (VUS) were identified. Using a structure-based approach, we defined a potential risk prediction method for VUS. This study describes the full landscape of GBA1-related parkinsonism in Luxembourg, showing a high prevalence of GBA1 variants as the major genetic risk for PD. Although the long-read DNA sequencing technique used in our study may be limited in its effectiveness to detect potential structural variants, our approach provides an important advancement for highly accurate GBA1 variant calling, which is essential for providing access to emerging causative therapies for GBA1 carriers.

引用

页数：14

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