Genetic landscape of Parkinson’s disease and related diseases in Luxembourg
ObjectivesTo explore the genetic architecture of PD in the Luxembourg Parkinson’s Study including cohorts of healthy people and patients with Parkinson’s disease (PD) and atypical parkinsonism (AP).Methods809 healthy controls, 680 PD and 103 AP were genotyped using the Neurochip array. We screened a...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2023.1282174/full |
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| author | Zied Landoulsi Sinthuja Pachchek Dheeraj Reddy Bobbili Lukas Pavelka Lukas Pavelka Patrick May Rejko Krüger Rejko Krüger Rejko Krüger the NCER-PD Consortium |
| author_facet | Zied Landoulsi Sinthuja Pachchek Dheeraj Reddy Bobbili Lukas Pavelka Lukas Pavelka Patrick May Rejko Krüger Rejko Krüger Rejko Krüger the NCER-PD Consortium |
| author_sort | Zied Landoulsi |
| collection | DOAJ |
| description | ObjectivesTo explore the genetic architecture of PD in the Luxembourg Parkinson’s Study including cohorts of healthy people and patients with Parkinson’s disease (PD) and atypical parkinsonism (AP).Methods809 healthy controls, 680 PD and 103 AP were genotyped using the Neurochip array. We screened and validated rare single nucleotide variants (SNVs) and copy number variants (CNVs) within seven PD-causing genes (LRRK2, SNCA, VPS35, PRKN, PARK7, PINK1 and ATP13A2). Polygenic risk scores (PRSs) were generated using the latest genome-wide association study for PD. We then estimated the role of common variants in PD risk by applying gene-set-specific PRSs.ResultsWe identified 60 rare SNVs in seven PD-causing genes, nine of which were pathogenic in LRRK2, PINK1 and PRKN. Eleven rare CNVs were detected in PRKN including seven duplications and four deletions. The majority of PRKN SNVs and CNVs carriers were heterozygous and not differentially distributed between cases and controls. The PRSs were significantly associated with PD and identified specific molecular pathways related to protein metabolism and signal transduction as drivers of PD risk.ConclusionWe performed a comprehensive genetic characterization of the deep-phenotyped individuals of the Luxembourgish Parkinson’s Study. Heterozygous SNVs and CNVs in PRKN were not associated with higher PD risk. In particular, we reported novel digenic variants in PD related genes and rare LRRK2 SNVs in AP patients. Our findings will help future studies to unravel the genetic complexity of PD. |
| first_indexed | 2024-03-08T21:46:20Z |
| format | Article |
| id | doaj.art-bba5dceb7aa64e058d0cb7efbed188ad |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-03-08T21:46:20Z |
| publishDate | 2023-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-bba5dceb7aa64e058d0cb7efbed188ad2023-12-20T09:05:37ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652023-12-011510.3389/fnagi.2023.12821741282174Genetic landscape of Parkinson’s disease and related diseases in LuxembourgZied Landoulsi0Sinthuja Pachchek1Dheeraj Reddy Bobbili2Lukas Pavelka3Lukas Pavelka4Patrick May5Rejko Krüger6Rejko Krüger7Rejko Krüger8the NCER-PD ConsortiumLCSB, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, LuxembourgLCSB, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, LuxembourgLCSB, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, LuxembourgParkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg, LuxembourgTransversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, LuxembourgLCSB, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, LuxembourgLCSB, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, LuxembourgParkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg, LuxembourgTransversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, LuxembourgObjectivesTo explore the genetic architecture of PD in the Luxembourg Parkinson’s Study including cohorts of healthy people and patients with Parkinson’s disease (PD) and atypical parkinsonism (AP).Methods809 healthy controls, 680 PD and 103 AP were genotyped using the Neurochip array. We screened and validated rare single nucleotide variants (SNVs) and copy number variants (CNVs) within seven PD-causing genes (LRRK2, SNCA, VPS35, PRKN, PARK7, PINK1 and ATP13A2). Polygenic risk scores (PRSs) were generated using the latest genome-wide association study for PD. We then estimated the role of common variants in PD risk by applying gene-set-specific PRSs.ResultsWe identified 60 rare SNVs in seven PD-causing genes, nine of which were pathogenic in LRRK2, PINK1 and PRKN. Eleven rare CNVs were detected in PRKN including seven duplications and four deletions. The majority of PRKN SNVs and CNVs carriers were heterozygous and not differentially distributed between cases and controls. The PRSs were significantly associated with PD and identified specific molecular pathways related to protein metabolism and signal transduction as drivers of PD risk.ConclusionWe performed a comprehensive genetic characterization of the deep-phenotyped individuals of the Luxembourgish Parkinson’s Study. Heterozygous SNVs and CNVs in PRKN were not associated with higher PD risk. In particular, we reported novel digenic variants in PD related genes and rare LRRK2 SNVs in AP patients. Our findings will help future studies to unravel the genetic complexity of PD.https://www.frontiersin.org/articles/10.3389/fnagi.2023.1282174/fullParkinson’s diseasegeneticsLuxembourgpolygenic risk scorecopy number variants |
| spellingShingle | Zied Landoulsi Sinthuja Pachchek Dheeraj Reddy Bobbili Lukas Pavelka Lukas Pavelka Patrick May Rejko Krüger Rejko Krüger Rejko Krüger the NCER-PD Consortium Genetic landscape of Parkinson’s disease and related diseases in Luxembourg Frontiers in Aging Neuroscience Parkinson’s disease genetics Luxembourg polygenic risk score copy number variants |
| title | Genetic landscape of Parkinson’s disease and related diseases in Luxembourg |
| title_full | Genetic landscape of Parkinson’s disease and related diseases in Luxembourg |
| title_fullStr | Genetic landscape of Parkinson’s disease and related diseases in Luxembourg |
| title_full_unstemmed | Genetic landscape of Parkinson’s disease and related diseases in Luxembourg |
| title_short | Genetic landscape of Parkinson’s disease and related diseases in Luxembourg |
| title_sort | genetic landscape of parkinson s disease and related diseases in luxembourg |
| topic | Parkinson’s disease genetics Luxembourg polygenic risk score copy number variants |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2023.1282174/full |
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