Genetic stratification of motor and QoL outcomes in Parkinson's disease in the EARLYSTIM study

Daniel Weiss; Zied Landoulsi; Patrick May; Manu Sharma; Michael Schüpbach; Hana You; Jean Christophe Corvol; Steffen Paschen; Ann-Kristin Helmers; Michael Barbe; Gereon Fink; Andrea A Kühn; Christine Brefel Courbon; Lars Wojtecki; Philippe Damier; Valerie Fraix; Jean-Luc Houeto; Jean Regis; Friederike Sixel-Döring; Marcus O Pinsker; Stephane Thobois; Alireza Gharabaghi; Valerie Stoker; Lars Timmermann; Alfons Schnitzler; Paul Krack; Marie Vidailhet; Günther Deuschl; Rejko Krüger

doi:10.1016/j.parkreldis.2022.08.025

Genetic stratification of motor and QoL outcomes in Parkinson's disease in the EARLYSTIM study

Parkinsonism Relat Disord. 2022 Oct:103:169-174. doi: 10.1016/j.parkreldis.2022.08.025. Epub 2022 Sep 8.

Authors

Daniel Weiss¹, Zied Landoulsi², Patrick May², Manu Sharma³, Michael Schüpbach⁴, Hana You⁵, Jean Christophe Corvol⁶, Steffen Paschen⁷, Ann-Kristin Helmers⁸, Michael Barbe⁹, Gereon Fink¹⁰, Andrea A Kühn¹¹, Christine Brefel Courbon¹², Lars Wojtecki¹³, Philippe Damier¹⁴, Valerie Fraix¹⁵, Jean-Luc Houeto¹⁶, Jean Regis¹⁷, Friederike Sixel-Döring¹⁸, Marcus O Pinsker¹⁹, Stephane Thobois²⁰, Alireza Gharabaghi²¹, Valerie Stoker²², Lars Timmermann²³, Alfons Schnitzler¹², Paul Krack²⁴, Marie Vidailhet⁴, Günther Deuschl⁷, Rejko Krüger²⁵

Affiliations

¹ Centre for Neurology, Department for Neurodegenerative Disease, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. Electronic address: daniel.weiss@uni-tuebingen.de.
² Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
³ Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.
⁴ Département de Neurologie, Hôpital Pitié-Salpêtrière, Centre d'Investigation Clinique 1422, Institut du Cerveau et de la Moelle Epinière, Institut National de Santé et en Recherche Médicale, Assistance Publique Hôpitaux de Paris, France; Institute of Neurology, Konolfingen, Switzerland; Department of Neurology, University Hospital Bern and University of Bern, Switzerland.
⁵ Department of Neurology, Inselspital University Hospital Bern and University of Bern, Switzerland.
⁶ Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, UMR 1127, Inserm 1127, CNRS7225, AP-HP, Department of Neurology, Salpetriere University Hospital, Paris, France.
⁷ Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de paris, Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France.
⁸ Department of Neurology, UKSH, Kiel Campus Christian-Albrechts-University, Kiel, Germany.
⁹ Department of Neurosurgery, UKSH Kiel, Kiel Campus Christian-Albrechts-University, Kiel, Germany.
¹⁰ Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Cognitive Neuroscience, Institute of Neuroscience and Medicine, Research Centre Jülich, Germany.
¹¹ Department of Neurology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
¹² Department of Neurology, INSERM Unite 1214, University Hospital Toulouse, France.
¹³ Institute of Clinical Neuroscience and Medical Psychology, Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
¹⁴ CHU Nantes, INSERM, CIC1413, Hôpital Laënnec, Nantes, France.
¹⁵ Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, 38000, Grenoble, France.
¹⁶ Department of Neurology, INSERM, Univ. Limoges, CHU Limoges, IRD, U1094 Tropical Neuroepidemiology, Institute of Epidemiology and Tropical Neurology, GEIST, Limoges, France.
¹⁷ Aix Marseille University Department of Functional Neurosurgery, CHU Timone, APHM, Marseille, France.
¹⁸ Paracelsus-Elena-Klinik Kassel, Kassel, Germany.
¹⁹ Division of Stereotactic and Functional Neurosurgery, University Medical Center, Freiburg, Freiburg, Germany.
²⁰ Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie C, Centre Expert Parkinson, Bron, France, France; Université Lyon, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Sud Charles Mérieux, Oullins, France.
²¹ Institute for Neuromodulation and Neurotechnology, University of Tübingen, Tübingen, Germany.
²² Medtronic, Minneapolis, MN, USA.
²³ Department of Neurology, University Hospital Marburg, Marburg, Germany.
²⁴ Department of Neurology, Bern University Hospital and University of Bern, Bern, Switzerland.
²⁵ Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg; Transversal Translational Medicine, Luxembourg Institute of Health, Strassen, Luxembourg; Parkinson Research Clinic, Centre Hospitalier de Luxembourg, Luxembourg.

PMID: 36117018
DOI: 10.1016/j.parkreldis.2022.08.025

Abstract

Purpose: The decision for subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease (PD) relies on clinical predictors. Whether genetic variables could predict favourable or unfavourable decisions is under investigation.

Objective: First, we aimed to reproduce the previous observation that SNCA rs356220 was associated with favourable STN-DBS motor response. In additional exploratory analyses, we studied if other PD risk and progression variants from the latest GWAS are associated with therapeutic outcome. Further, we evaluated the predictive value of polygenic risk scores.

Methods: We comprehensively genotyped patients from the EarlyStim cohort using NeuroChip, and assessed the clinico-genetic associations with longitudinal outcome parameters.

Results: The SNCA rs356220 variant did not predict UPDRS III outcomes. However, it was associated with quality of life improvement in secondary analyses. Several polymorphisms from previously identified GWAS hits predicted motor or quality of life outcomes in DBS patients. Polygenic risk scores did not predict any outcome parameter.

Conclusions: Our findings support the hypothesis that different common genetic markers are associated with favourable quality of life outcomes of STN-DBS in PD. These findings can be the basis for further validation in larger and independent cohorts.

Keywords: Alpha-synuclein; Deep brain stimulation; Genetic association; Parkinson's disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Deep Brain Stimulation*
Genetic Markers
Humans
Parkinson Disease* / complications
Parkinson Disease* / genetics
Parkinson Disease* / therapy
Quality of Life
Subthalamic Nucleus* / physiology
Treatment Outcome

Substances

Genetic Markers