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GWAS risk factors in Parkinson's disease : LRRK2 coding variation and genetic interaction with PARK16

Soto-Ortolaza, A. I. ; Heckman, M. G. ; Labbe, C. ; Serie, D. J. ; Puschmann, Andreas LU orcid ; Rayaprolu, S. ; Strongosky, A. ; Boczarska-Jedynak, M. ; Opala, G. and Krygowska-Wajs, A. , et al. (2013) In American Journal of Neurodegenerative Disease 2(4). p.99-287
Abstract

Parkinson's disease (PD) is a multifactorial movement disorder characterized by progressive neurodegeneration. Genome-wide association studies (GWAS) have nominated over fifteen distinct loci associated with risk of PD, however the biological mechanisms by which these loci influence disease risk are mostly unknown. GWAS are only the first step in the identification of disease genes: the specific causal variants responsible for the risk within the associated loci and the interactions between them must be identified to fully comprehend their impact on the development of PD. In the present study, we first attempted to replicate the association signals of 17 PD GWAS loci in our series of 1381 patients with PD and 1328 controls. BST1, SNCA,... (More)

Parkinson's disease (PD) is a multifactorial movement disorder characterized by progressive neurodegeneration. Genome-wide association studies (GWAS) have nominated over fifteen distinct loci associated with risk of PD, however the biological mechanisms by which these loci influence disease risk are mostly unknown. GWAS are only the first step in the identification of disease genes: the specific causal variants responsible for the risk within the associated loci and the interactions between them must be identified to fully comprehend their impact on the development of PD. In the present study, we first attempted to replicate the association signals of 17 PD GWAS loci in our series of 1381 patients with PD and 1328 controls. BST1, SNCA, HLA-DRA, CCDC62/HIP1R and MAPT all showed a significant association with PD under different models of inheritance and LRRK2 showed a suggestive association. We then examined the role of coding LRRK2 variants in the GWAS association signal for that gene. The previously identified LRRK2 risk mutant p.M1646T and protective haplotype p.N551K-R1398H-K1423K did not explain the association signal of LRRK2 in our series. Finally, we investigated the gene-gene interaction between PARK16 and LRRK2 that has previously been proposed. We observed no interaction between PARK16 and LRRK2 GWAS variants, but did observe a non-significant trend toward interaction between PARK16 and LRRK2 variants within the protective haplotype. Identification of causal variants and the interactions between them is the crucial next step in making biological sense of the massive amount of data generated by GWAS studies. Future studies combining larger sample sizes will undoubtedly shed light on the complex molecular interplay leading to the development of PD.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Association studies in genetics, Parkinson's disease/Parkinsonism
in
American Journal of Neurodegenerative Disease
volume
2
issue
4
pages
13 pages
publisher
e-Century Publishing
external identifiers
  • scopus:84980052864
  • pmid:24319646
ISSN
2165-591X
language
English
LU publication?
yes
additional info
4
id
adb5390c-5bf1-42b5-ac20-ae7c8a3a62f3 (old id 7374363)
alternative location
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852568/pdf/ajnd0002-0287.pdf
date added to LUP
2016-04-01 13:00:33
date last changed
2023-11-12 09:58:00
@article{adb5390c-5bf1-42b5-ac20-ae7c8a3a62f3,
  abstract     = {{<p>Parkinson's disease (PD) is a multifactorial movement disorder characterized by progressive neurodegeneration. Genome-wide association studies (GWAS) have nominated over fifteen distinct loci associated with risk of PD, however the biological mechanisms by which these loci influence disease risk are mostly unknown. GWAS are only the first step in the identification of disease genes: the specific causal variants responsible for the risk within the associated loci and the interactions between them must be identified to fully comprehend their impact on the development of PD. In the present study, we first attempted to replicate the association signals of 17 PD GWAS loci in our series of 1381 patients with PD and 1328 controls. BST1, SNCA, HLA-DRA, CCDC62/HIP1R and MAPT all showed a significant association with PD under different models of inheritance and LRRK2 showed a suggestive association. We then examined the role of coding LRRK2 variants in the GWAS association signal for that gene. The previously identified LRRK2 risk mutant p.M1646T and protective haplotype p.N551K-R1398H-K1423K did not explain the association signal of LRRK2 in our series. Finally, we investigated the gene-gene interaction between PARK16 and LRRK2 that has previously been proposed. We observed no interaction between PARK16 and LRRK2 GWAS variants, but did observe a non-significant trend toward interaction between PARK16 and LRRK2 variants within the protective haplotype. Identification of causal variants and the interactions between them is the crucial next step in making biological sense of the massive amount of data generated by GWAS studies. Future studies combining larger sample sizes will undoubtedly shed light on the complex molecular interplay leading to the development of PD.</p>}},
  author       = {{Soto-Ortolaza, A. I. and Heckman, M. G. and Labbe, C. and Serie, D. J. and Puschmann, Andreas and Rayaprolu, S. and Strongosky, A. and Boczarska-Jedynak, M. and Opala, G. and Krygowska-Wajs, A. and Barcikowska, M. and Czyzewski, K. and Lynch, T. and Uitti, R. J. and Wszolek, Z. K. and Ross, O. A.}},
  issn         = {{2165-591X}},
  keywords     = {{Association studies in genetics; Parkinson's disease/Parkinsonism}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{99--287}},
  publisher    = {{e-Century Publishing}},
  series       = {{American Journal of Neurodegenerative Disease}},
  title        = {{GWAS risk factors in Parkinson's disease : LRRK2 coding variation and genetic interaction with PARK16}},
  url          = {{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852568/pdf/ajnd0002-0287.pdf}},
  volume       = {{2}},
  year         = {{2013}},
}