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Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease
Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease
We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10-16). We also show six risk loci associated with proximal gene expression or DNA methylation.
1061-4036
989-993
Nalls, Mike A.
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Pankratz, Nathan
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Stefansson, Kari
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Hardy, John A.
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Heutink, Peter
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Wood, Nicholas W.
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Houlden, Henry
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International Parkinson's Disease Genomics Consortium (IPDGC)
Parkinson’s Study Group (PSG)
Parkinson’s Research: The Organized GENetics Initiative (PROGENI)
23andMe
GenePD
NeuroGenetics Research Consortium (NGRC)
Hussman Institute of Human Genomics (HIHG)
The Ashkenazi Jewish Dataset Investigator
Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE)
North American Brain Expression Consortium (NABEC)
United Kingdom Brain Expression Consortium (UKBEC)
Greek Parkinson’s Disease Consortium
Alzheimer Genetic Analysis Group
Nalls, Mike A.
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Pankratz, Nathan
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Lill, Christina M.
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Do, Chuong B.
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Schulte, Claudia
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Arepalli, Sampath
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Ioannidis, John P.A.
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Hadjigeorgiou, Georgios M.
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Bis, Joshua C.
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Martinez, Maria
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Perlmutter, Joel S.
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Marder, Karen
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Fiske, Brian
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Sutherland, Margaret
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Hardy, John A.
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Heutink, Peter
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Chen, Honglei
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Wood, Nicholas W.
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Houlden, Henry
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Gasser, Thomas
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Bertram, Lars
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Eriksson, Nicholas
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Foroud, Tatiana
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Morrison, Karen
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Nalls, Mike A., Pankratz, Nathan and Lill, Christina M. , International Parkinson's Disease Genomics Consortium (IPDGC), Parkinson’s Study Group (PSG) and Parkinson’s Research: The Organized GENetics Initiative (PROGENI) et al. (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nature Genetics, 46 (9), 989-993. (doi:10.1038/ng.3043).

Record type: Article

Abstract

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10-16). We also show six risk loci associated with proximal gene expression or DNA methylation.

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More information

Accepted/In Press date: 30 June 2014
e-pub ahead of print date: 27 July 2014
Published date: 1 September 2014
Organisations: Medical Education

Identifiers

Local EPrints ID: 398209
URI: http://eprints.soton.ac.uk/id/eprint/398209
DOI: doi:10.1038/ng.3043
ISSN: 1061-4036
PURE UUID: 931fedba-0ee0-4036-8ff4-859c1e2a6ce3
ORCID for Karen Morrison: ORCID iD orcid.org/0000-0003-0216-5717

Catalogue record

Date deposited: 20 Jul 2016 14:19
Last modified: 17 Mar 2024 14:01

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Contributors

Author: Mike A. Nalls
Author: Nathan Pankratz
Author: Christina M. Lill
Author: Chuong B. Do
Author: Dena G. Hernandez
Author: Mohamad Saad
Author: Anita L. DeStefano
Author: Eleanna Kara
Author: Jose Bras
Author: Manu Sharma
Author: Claudia Schulte
Author: Margaux F. Keller
Author: Sampath Arepalli
Author: Christopher Letson
Author: Connor Edsall
Author: Hreinn Stefansson
Author: Xinmin Liu
Author: Hannah Pliner
Author: Joseph H. Lee
Author: Rong Cheng
Author: M Arfan Ikram
Author: John P.A. Ioannidis
Author: Georgios M. Hadjigeorgiou
Author: Joshua C. Bis
Author: Maria Martinez
Author: Joel S. Perlmutter
Author: Alison Goate
Author: Karen Marder
Author: Brian Fiske
Author: Margaret Sutherland
Author: Georgia Xiromerisiou
Author: Richard H. Myers
Author: Lorraine N. Clark
Author: Kari Stefansson
Author: John A. Hardy
Author: Peter Heutink
Author: Honglei Chen
Author: Nicholas W. Wood
Author: Henry Houlden
Author: Haydeh Payami
Author: Alexis Brice
Author: William K. Scott
Author: Thomas Gasser
Author: Lars Bertram
Author: Nicholas Eriksson
Author: Tatiana Foroud
Author: Andrew B. Singleton
Author: Karen Morrison ORCID iD
Corporate Author: International Parkinson's Disease Genomics Consortium (IPDGC)
Corporate Author: Parkinson’s Study Group (PSG)
Corporate Author: Parkinson’s Research: The Organized GENetics Initiative (PROGENI)
Corporate Author: 23andMe
Corporate Author: GenePD
Corporate Author: NeuroGenetics Research Consortium (NGRC)
Corporate Author: Hussman Institute of Human Genomics (HIHG)
Corporate Author: The Ashkenazi Jewish Dataset Investigator
Corporate Author: Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE)
Corporate Author: North American Brain Expression Consortium (NABEC)
Corporate Author: United Kingdom Brain Expression Consortium (UKBEC)
Corporate Author: Greek Parkinson’s Disease Consortium
Corporate Author: Alzheimer Genetic Analysis Group

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