Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence from the COURAGE-PD Consortium
Grover, S. ; Puschmann, A. LU
; Hellberg, C.
LU
and Sharma, M.
(2022)
In Neurology
99(7).
p.698-710
- Abstract
- Background and Objectives Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. Methods A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics... (More)
- Background and Objectives Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. Methods A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). Results The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), pCOURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), pCOURAGE+IPDGC = 3.13 × 10-9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = -0.526(0.096), pCOURAGE+IPDGC = 4.41 × 10-8). Discussion Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD. © American Academy of Neurology. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/6e85247c-3ace-46d9-a3e7-41b40c54c468
- author
- Grover, S.
; Puschmann, A.
LU
; Hellberg, C.
LU
and Sharma, M.
- author collaboration
- organization
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- courage, female, genetic predisposition, genetics, genome-wide association study, human, meta analysis, onset age, Parkinson disease, single nucleotide polymorphism, Age of Onset, Courage, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Parkinson Disease, Polymorphism, Single Nucleotide
- in
- Neurology
- volume
- 99
- issue
- 7
- pages
- 698 - 710
- publisher
- Lippincott Williams & Wilkins
- external identifiers
-
- scopus:85136019610
- ISSN
- 0028-3878
- DOI
- 10.1212/WNL.0000000000200699
- language
- English
- LU publication?
- yes
- id
- 6e85247c-3ace-46d9-a3e7-41b40c54c468
- date added to LUP
- 2022-09-16 10:42:55
- date last changed
- 2023-12-03 16:03:41
@article{6e85247c-3ace-46d9-a3e7-41b40c54c468,
abstract = {{Background and Objectives Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. Methods A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). Results The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), pCOURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), pCOURAGE+IPDGC = 3.13 × 10-9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = -0.526(0.096), pCOURAGE+IPDGC = 4.41 × 10-8). Discussion Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD. © American Academy of Neurology.}},
author = {{Grover, S. and Puschmann, A. and Hellberg, C. and Sharma, M.}},
issn = {{0028-3878}},
keywords = {{courage; female; genetic predisposition; genetics; genome-wide association study; human; meta analysis; onset age; Parkinson disease; single nucleotide polymorphism; Age of Onset; Courage; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Parkinson Disease; Polymorphism, Single Nucleotide}},
language = {{eng}},
number = {{7}},
pages = {{698--710}},
publisher = {{Lippincott Williams & Wilkins}},
series = {{Neurology}},
title = {{Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence from the COURAGE-PD Consortium}},
url = {{http://dx.doi.org/10.1212/WNL.0000000000200699}},
doi = {{10.1212/WNL.0000000000200699}},
volume = {{99}},
year = {{2022}},
}