Article Dans Une Revue Movement Disorders Année : 2019

Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms

1 NIA - National Institute on Aging [Bethesda, USA]
2 NINDS - National Institute of Neurological Disorders and Stroke [Bethesda]
3 23andMe Inc.
4 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
5 University of Maryland School of Medicine
6 Oslo University Hospital [Oslo]
7 DZNE - Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm]
8 Hertie Institute for Clinical Brain Research [Tubingen]
9 Eberhard Karls Universität Tübingen = University of Tübingen
10 McGill University = Université McGill [Montréal, Canada]
11 Montreal Neurological Institute and Hospital
12 University of Oulu [Finland] = Oulun yliopisto [Suomi] = Université d'Oulu [Finlande]
13 OUH, OYKS, OYS - Oulu University Central Hospital [Finland] = Oulun yliopistollinen keskussairaala [Suomi] = Oulun yliopistollinen sairaala [Suomi]
14 The Michael J Fox Foundation for Parkinson's Research
15 QMUL - Queen Mary University of London
16 UCL Queen Square Institute of Neurology
17 Baylor College of Medecine
18 ICM - Institut du Cerveau = Paris Brain Institute
19 LUMC - Leiden University Medical Center
20 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
21 HUS - Helsinki University Hospital [Finland]
22 Institute of Clinical Medicine [Oslo]
23 Queen Elizabeth University Hospital (Glasgow)
24 University of Glasgow
25 BCM - Baylor College of Medicine
26 Texas Children's Hospital [Houston, USA]
27 UCL Institute of Neurology, Queen Square [London]
28 Queensland Brain Institute
Karl Heilbron
  • Fonction : Auteur
Alexis Brice
David Hinds
  • Fonction : Auteur

Résumé

Background: Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives: To identify the genetic determinants of PD age at onset. Methods: Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. Results: We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions: Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. © 2019 International Parkinson and Movement Disorder Society.

Dates et versions

hal-04560836 , version 1 (26-04-2024)

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Citer

Cornelis Blauwendraat, Karl Heilbron, Costanza Vallerga, Sara Bandres-Ciga, Rainer von Coelln, et al.. Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms. Movement Disorders, 2019, 34 (6), pp.866-875. ⟨10.1002/mds.27659⟩. ⟨hal-04560836⟩
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