Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson's disease

  • Giuseppe Arena (Contributor)
  • Zied Landoulsi (Contributor)
  • Dajana Grossmann (Contributor)
  • Armelle Vitali (Contributor)
  • Sylvie Delcambre (Contributor)
  • Alexandre Baron (Contributor)
  • Paul Antony (Contributor)
  • Ibrahim Boussaad (Contributor)
  • Dheeraj Reddy Bobbili (Contributor)
  • Ashwin Ashok Kumar Sreelatha (Contributor)
  • Lukas Pavelka (Contributor)
  • Christine Klein (Contributor)
  • Philip Seibler (Contributor)
  • Enrico Glaab (Contributor)
  • Manu Sharma (Contributor)
  • Rejko Krüger (Contributor)
  • Patrick May (Contributor)
  • Anne Grünewald (Contributor)
  • Alexander Hundt (Contributor)
  • Alexandre Bisdorff (Contributor)
  • Amir Sharify (Contributor)
  • Anne-Marie Hanff (Contributor)
  • Armin Rauschenberger (Contributor)
  • Beatrice Nicolai (Contributor)
  • Brit Mollenhauer (Contributor)
  • Camille Bellora (Contributor)
  • Carlos Moreno (Contributor)
  • Chouaib Mediouni (Contributor)
  • Christophe Trefois (Contributor)
  • Claire Pauly (Contributor)
  • Clare Mackay (Contributor)
  • Clarissa Gomes (Contributor)
  • Daniela Berg (Contributor)
  • Daniela Esteves (Contributor)
  • Deborah McIntyre (Contributor)
  • Dheeraj Reddy Bobbili (Contributor)
  • Eduardo Rosales (Contributor)
  • Ekaterina Soboleva (Contributor)
  • Elisa Gómez De Lope (Contributor)
  • Elodie Thiry (Contributor)
  • Estelle Henry (Contributor)
  • Estelle Sandt (Contributor)
  • Evi Wollscheid-Lengeling (Contributor)
  • Francoise Meisch (Contributor)
  • Friedrich Mühlschlegel (Contributor)
  • Gaël Hammot (Contributor)
  • Geeta Acharya (Contributor)
  • Gelani Zelimkhanov (Contributor)
  • Gessica Contesotto (Contributor)
  • Gloria Aguayo (Contributor)
  • Guilherme Marques (Contributor)
  • Guy Berchem (Contributor)
  • Guy Fagherazzi (Contributor)
  • Hermann Thien (Contributor)
  • Inga Liepelt (Contributor)
  • Isabel Rosety (Contributor)
  • Jacek Jaroslaw Lebioda (Contributor)
  • Jean-Edouard Schweitzer (Contributor)
  • Jean-Paul Nicolay (Contributor)
  • Jean-Yves Ferrand (Contributor)
  • Jens C. Schwamborn (Contributor)
  • Jérôme Graas (Contributor)
  • Jessica Calmes (Contributor)
  • Jochen Klucken (Contributor)
  • Johanna Trouet (Contributor)
  • Kate Sokolowska (Contributor)
  • Kathrin Brockmann (Contributor)
  • Katrin Marcus (Contributor)
  • Katy Beaumont (Contributor)
  • Kirsten Rump (Contributor)
  • Laura Longhino (Contributor)
  • Laure Pauly (Contributor)
  • Liliana Vilas Boas (Contributor)
  • Linda Hansen (Contributor)
  • Lorieza Castillo (Contributor)
  • Magali Perquin (Contributor)
  • Maharshi Vyas (Contributor)
  • Manon Gantenbein (Contributor)
  • Marek Ostaszewski (Contributor)
  • Margaux Schmitt (Contributor)
  • Mariella Graziano (Contributor)
  • Marijus Giraitis (Contributor)
  • Maura Minelli (Contributor)
  • Maxime Hansen (Contributor)
  • Mesele Valenti (Contributor)
  • Michael T. Heneka (Contributor)
  • Michael Heymann (Contributor)
  • Michel Mittelbronn (Contributor)
  • Michel Vaillant (Contributor)
  • Michele Bassis (Contributor)
  • Michele Hu (Contributor)
  • Muhammad Ali (Contributor)
  • Myriam Alexandre (Contributor)
  • Myriam Menster (Contributor)
  • Nadine Jacoby (Contributor)
  • Nico J. Diederich (Contributor)
  • Olena Tsurkalenko (Contributor)
  • Olivier Terwindt (Contributor)
  • Patricia Martins Conde (Contributor)
  • Paul Wilmes (Contributor)
  • Paula Cristina Lupu (Contributor)
  • Pauline Lambert (Contributor)
  • Piotr Gawron (Contributor)
  • Quentin Klopfenstein (Contributor)
  • Rajesh Rawal (Contributor)
  • Rebecca Ting Jiin Loo (Contributor)
  • Regina Becker (Contributor)
  • Reinhard Schneider (Contributor)
  • Rene Dondelinger (Contributor)
  • Richard Wade-Martins (Contributor)
  • Robert Liszka (Contributor)
  • Romain Nati (Contributor)
  • Rosalina Ramos Lima (Contributor)
  • Roseline Lentz (Contributor)
  • Rudi Balling (Contributor)
  • Sabine Schmitz (Contributor)
  • Sarah Nickels (Contributor)
  • Sascha Herzinger (Contributor)
  • Sinthuja Pachchek (Contributor)
  • Soumyabrata Ghosh (Contributor)
  • Stefano Sapienza (Contributor)
  • Sylvia Herbrink (Contributor)
  • Tainá Marques (Contributor)
  • Thomas Gasser (Contributor)
  • Ulf Nehrbass (Contributor)
  • Valentin Groues (Contributor)
  • Venkata Satagopam (Contributor)
  • Victoria Lorentz (Contributor)
  • Walter Maetzler (Contributor)
  • Wei Gu (Contributor)
  • Wim Ammerlann (Contributor)
  • Yohan Jaroz (Contributor)
  • Sulev Koks (Contributor)
  • George D. Mellick (Contributor)
  • Walter Pirker (Contributor)
  • Alexander Zimprich (Contributor)
  • Anthony E. Lang (Contributor)
  • Ekaterina Rogaeva (Contributor)
  • Pille Taba (Contributor)
  • A. Brice (Contributor)
  • Marie Christine Chartier-Harlin (Contributor)
  • Jean Christophe Corvol (Contributor)
  • Cloé Domenighetti (Contributor)
  • Alexis Elbaz (Contributor)
  • S. Lesage (Contributor)
  • Eugénie Mutez (Contributor)
  • Pierre Emmanuel Sugier (Contributor)
  • Sandeep Grover (Contributor)
  • Kathrin Brockmann (Contributor)
  • Angela B. Deutschländer (Contributor)
  • T. Gasser (Contributor)
  • Jens Krüger (Contributor)
  • Peter Lichtner (Contributor)
  • Milena Radivojkov-Blagojevic (Contributor)
  • Claudia Schulte (Contributor)
  • Manu Sharma (Contributor)
  • Efthimos Dardiotis (Contributor)
  • Georges M. Hadjigeorgiou (Contributor)
  • Athina Maria Simitsi (Contributor)
  • Leonidas Stefanis (Contributor)
  • Grazia Annesi (Contributor)
  • Laura Brighina (Contributor)
  • Carlo Ferrarese (Contributor)
  • Simona Petrucci (Contributor)
  • Gianni Pezzoli (Contributor)
  • Andrea Quattrone (Contributor)
  • Letizia Straniero (Contributor)
  • Monica Gagliardi (Contributor)
  • Enza Maria Valente (Contributor)
  • Anna Zecchinelli (Contributor)
  • Nobotaka Hattori (Contributor)
  • Akiyoshi Nakayama (Contributor)
  • Hirotaka Matsuo (Contributor)
  • Kenya Nishioka (Contributor)
  • Dheeraj R. Bobbili (Contributor)
  • Bastiaan R. Bloem (Contributor)
  • Bart van de Warrenburg (Contributor)
  • Jan Aasly (Contributor)
  • Lasse Pihlstrom (Contributor)
  • Mathias Toft (Contributor)
  • Joaquim J. Ferreira (Contributor)
  • Leonor Correia Guedes (Contributor)
  • Soraya Bardien (Contributor)
  • Jonathan Carr (Contributor)
  • Sun Ju Chung (Contributor)
  • Yun Joong Kim (Contributor)
  • Monica Diez-Fairen (Contributor)
  • Mario Ezquerra (Contributor)
  • Pau Pastor (Contributor)
  • Eduardo Tolosa (Contributor)
  • Andrea C. Belin (Contributor)
  • Nancy L. Pedersen (Contributor)
  • Andreas Puschmann (Contributor)
  • Caroline Ran (Contributor)
  • Emil Y. Rodstrom (Contributor)
  • Karin Wirdefeldt (Contributor)
  • Carl E. Clarke (Contributor)
  • K. E. Morrison (Contributor)
  • Manuela Tan (Contributor)
  • Connor Edsall (Contributor)
  • Matthew J. Farrer (Contributor)
  • Dimitri Krainc (Contributor)
  • Andrew B. Singleton (Contributor)
  • Lena F. Burbulla (German Center for Neurodegenerative Diseases, Northwestern University, Munich Cluster for Systems Neurology (SyNergy), Ludwig Maximilian University of Munich) (Contributor)
  • Dena G. Hernandez (Contributor)
  • The NCER-PD and COURAGE-PD Consortia (Creator)

Dataset

Description

Background Parkinson’s disease (PD) is the fastest growing neurodegenerative disorder, with affected individuals expected to double during the next 20 years. This raises the urgent need to better understand the genetic architecture and downstream cellular alterations underlying PD pathogenesis, in order to identify more focused therapeutic targets. While only ∼10% of PD cases can be clearly attributed to monogenic causes, there is mounting evidence that additional genetic factors could play a role in idiopathic PD (iPD). In particular, common variants with low to moderate effect size in multiple genes regulating key neuroprotective activities may act as risk factors for PD. In light of the well-established involvement of mitochondrial dysfunction in PD, we hypothesized that a fraction of iPD cases may harbour a pathogenic combination of common variants in nuclear-encoded mitochondrial genes, ultimately resulting in neurodegeneration. Methods to capture this mitochondria-related “missing heritability”, we leveraged on existing data from previous genome-wide association studies (GWAS) – i.e., the large PD GWAS from Nalls and colleagues. We then used computational approaches based on mitochondria-specific polygenic risk scores (mitoPRSs) for imputing the genotype data obtained from different iPD case-control datasets worldwide, including the Luxembourg Parkinson’s Study (412 iPD patients and 576 healthy controls) and the COURAGE-PD cohorts (7270 iPD cases and 6819 healthy controls). Results applying this approach to gene sets controlling mitochondrial pathways potentially relevant for neurodegeneration in PD, we demonstrated that common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk both in the Luxembourg Parkinson’s Study (odds ratio, OR=1.31[1.14-1.50], p=5.4e-04) and in COURAGE-PD (OR=1.23[1.18-1.27], p=1.5e-29). Functional analyses in primary skin fibroblasts and in the corresponding induced pluripotent stem cells-derived neuronal progenitor cells from Luxembourg Parkinson’s Study iPD patients stratified according to the OXPHOS-PRS, revealed significant differences in mitochondrial respiration between high and low risk groups (p < 0.05). Finally, we also demonstrated that iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients. Conclusions our findings suggest that OXPHOS-PRS may represent a promising strategy to stratify iPD patients into pathogenic subgroups – in which the underlying neurodegeneration is due to a genetically defined mitochondrial burden – potentially eligible for future, more tailored mitochondrially targeted treatments.
Date made available2023
PublisherZENODO

Cite this