Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms.
Adult
Age of Onset
Aged
Aged, 80 and over
Alleles
Databases, Genetic
Female
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Glucosylceramidase
/ genetics
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
/ genetics
Male
Middle Aged
Parkinson Disease
/ genetics
Polymorphism, Single Nucleotide
Young Adult
alpha-Synuclein
/ genetics
GBA
Parkinson's disease
SNCA
TMEM175
age at onset
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
30
11
2018
revised:
02
01
2019
accepted:
21
01
2019
pubmed:
9
4
2019
medline:
14
3
2020
entrez:
9
4
2019
Statut:
ppublish
Résumé
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. To identify the genetic determinants of PD age at onset. Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. 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. 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.
Sections du 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.
Identifiants
pubmed: 30957308
doi: 10.1002/mds.27659
pmc: PMC6579628
mid: NIHMS1017873
doi:
Substances chimiques
SNCA protein, human
0
alpha-Synuclein
0
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
GBA protein, human
EC 3.2.1.45
Glucosylceramidase
EC 3.2.1.45
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
866-875Subventions
Organisme : Medical Research Council
ID : MR/K01417X/1
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA141668
Pays : United States
Organisme : Medical Research Council
ID : MR/L501542/1
Pays : United Kingdom
Organisme : Intramural NIH HHS
ID : Z01 ES101986
Pays : United States
Organisme : Parkinson's UK
ID : G-0907
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1001799
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N026004/1
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R01 NS037167
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA NS003154
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 AG000949-02
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Parkinson's UK
ID : J-1101
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0701075
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0901254
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : P50 NS071674
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 AG000932-01
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 AG000949
Pays : United States
Informations de copyright
© 2019 International Parkinson and Movement Disorder Society.
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