[en] Background
Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder shaped by, amongst others, high-impact variants and common polygenic factors. The Personalized Parkinson Project (PPP) offers deep phenotyping and longitudinal follow-up of Dutch people with PD. Here, we characterize the genetic landscape and its interaction with lifestyle factors within PPP.
Methods
We utilized three complementary approaches in N=507 persons with PD: 1) short-read PD gene panel sequencing of eight PD genes, 2) genome-wide genotyping array, and 3) targeted long-read sequencing of the GBA1 gene. Additionally, we calculated the mitochondrial-function polygenic score (MGS). Associations between genetic factors, smoking status, and age at onset (AAO) were assessed using non-parametric tests, correlation analyses, and multiple regression models.
Results
Genetic screening of the participants revealed N=79 GBA1 (∼15%), N=3 LRRK2, N=1 CHCHD2, N=1 SNCA variant carrier, and N=9 heterozygous PRKN/PINK1 variants. We also observed an interaction between MGS and smoking: MGS was associated with earlier AAO in non-smokers in persons with iPD (N=414, β=-1.87, p=0.038).
Conclusion
Our findings corroborate previously reported frequencies of variants in PD-associated genes in European populations, and suggest a potential association between smoking and a mitochondrial dysfunction signature in PD. Thus, even in persons without rare variants (iPD subgroup), complex genetic contributions remained relevant. Our study supports future downstream stratification and personalized medicine approaches with high-impact variants and polygenic risk scores.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes Neurology
Author, co-author :
Lüth, Theresa; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Klein, Christine; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Helmich, Rick C. ; Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Center of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands
Brüggemann, Norbert; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany ; Section of Movement Disorders, Department of Neurology, University of Lübeck, Lübeck, Germany
Hrir, Sana; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Kuiperij, H. Bea; Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Center of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands
GORGOGIETAS, Vyron ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Gomes Fernandes, Sara Beatriz; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
Prasuhn, Jannik; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany ; Section of Movement Disorders, Department of Neurology, University of Lübeck, Lübeck, Germany
Outeiro, Tiago F.; University Medical Center Göttingen, Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Göttingen, Germany
Steidel, Kenan; Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Center of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands ; Neurology Department at Medical Faculty Marburg, Philipps-University Marburg, Marburg, Germany
LANDOULSI, Zied ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Bioinformatics Core > Research BioCore ; Luxembourg Institute of Health, Strassen, Luxembourg, and Centre Hospitalier de Luxembourg, City of Luxembourg, Luxembourg
Kleinz, Teresa; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany ; Section of Movement Disorders, Department of Neurology, University of Lübeck, Lübeck, Germany
Schaake, Susen; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
Much, Christoph; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
KRÜGER, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience ; Luxembourg Institute of Health, Strassen, Luxembourg, and Centre Hospitalier de Luxembourg, City of Luxembourg, Luxembourg
Verbeek, Marcel M.; Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Center of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands ; Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands
Bloem, Bastiaan R.; Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Center of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands
van de Warrenburg, Bart P.; Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Center of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands
Trinh, Joanne; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
MJFF - Michael J. Fox Foundation for Parkinson's Research
Funding text :
The study was supported by funding from the Joint Programme of Neurodegenerative Diseases (JPND, ControlPD), by ZonMw Open (MiGut, Project number: 09120012110098) and by the Deutsche Forschungsgemeinschaft with a Heisenberg Grant (TR 1714/7-1) to JT. ZL and PM were supported by the FUN-MITO grant by the Michael J. Fox Foundation (MJFF).
