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

doi:10.1038/ng.3043

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

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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.

Original language	English
Pages (from-to)	989-993
Number of pages	5
Journal	Nature Genetics
Volume	46
Issue number	9
DOIs	https://doi.org/10.1038/ng.3043
State	Published - Jan 1 2014

Bibliographical note

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© 2014 Nature America, Inc. All rights reserved.

Funding

Funders	Funder number
National Institutes of Health (NIH)	K23NS070867, R44HG006981, R01NS088538, UL1TR001108, P50NS038377
National Institutes of Health/National Institute of Environmental Health Sciences	ZIAES101986
UK Medical Research Council, Engineering and Physical Sciences Research Council	G1001253, MC_PC_09003, MR/L501554/1, G108/638, G0802760, G0701075, MC_G1000735, MC_G0901330, G1100479, G0802462, MR/L010305/1, MR/J004758/1, MR/L016400/1, G0901254, G0700943
National Institute on Aging	U24AG021886, R01AG033193, ZIAAG000932, R01AG023629, P30AG013846, R01AG025259, ZIAAG000949, R01AG031287, R01AG016495, R01AG008122, K23AG024826
National Center for Research Resources	KL2RR024154, UL1RR024156
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	K23NS070867, P50NS071674, R21NS050487, R01NS017950, R01NS075321, R01NS037167, R01NS076843, R01NS036960, K02NS073836, R01NS088538, P50NS038377, R56NS036630
National Center for Advancing Translational Sciences (NCATS)	UL1TR000124, UL1TR001108, UL1TR002529
National Heart, Lung, and Blood Institute (NHLBI)	R01HL120393
National Institute of Diabetes and Digestive and Kidney Diseases	P30DK063491
National Human Genome Research Institute	R44HG006981
National Childhood Cancer Registry – National Cancer Institute	R01CA141668

ASJC Scopus subject areas

Genetics

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@article{2354e268681f4eeda809ebdd8c255a5f,

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

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.",

author = "Nalls, \{Mike A.\} and Nathan Pankratz and Lill, \{Christina M.\} and Do, \{Chuong B.\} and Hernandez, \{Dena G.\} and Mohamad Saad and Destefano, \{Anita L.\} and Eleanna Kara and Jose Bras and Manu Sharma and Claudia Schulte and Keller, \{Margaux F.\} and Sampath Arepalli and Christopher Letson and Connor Edsall and Hreinn Stefansson and Xinmin Liu and Hannah Pliner and Lee, \{Joseph H.\} and Rong Cheng and Ikram, \{M. Arfan\} and Ioannidis, \{John P.A.\} and Hadjigeorgiou, \{Georgios M.\} and Bis, \{Joshua C.\} and Maria Martinez and Perlmutter, \{Joel S.\} and Alison Goate and Karen Marder and Brian Fiske and Margaret Sutherland and Georgia Xiromerisiou and Myers, \{Richard H.\} and Clark, \{Lorraine N.\} and Kari Stefansson and Hardy, \{John A.\} and Peter Heutink and Honglei Chen and Wood, \{Nicholas W.\} and Henry Houlden and Haydeh Payami and Alexis Brice and Scott, \{William K.\} and Thomas Gasser and Lars Bertram and Nicholas Eriksson and Tatiana Foroud and Singleton, \{Andrew B.\} and Vincent Plagnol and Sheerin, \{Una Marie\} and J. Slevin",

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AU - Pankratz, Nathan

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AU - Do, Chuong B.

AU - Hernandez, Dena G.

AU - Saad, Mohamad

AU - Destefano, Anita L.

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AU - Sharma, Manu

AU - Schulte, Claudia

AU - Keller, Margaux F.

AU - Arepalli, Sampath

AU - Letson, Christopher

AU - Edsall, Connor

AU - Stefansson, Hreinn

AU - Liu, Xinmin

AU - Pliner, Hannah

AU - Lee, Joseph H.

AU - Cheng, Rong

AU - Ikram, M. Arfan

AU - Ioannidis, John P.A.

AU - Hadjigeorgiou, Georgios M.

AU - Bis, Joshua C.

AU - Martinez, Maria

AU - Perlmutter, Joel S.

AU - Goate, Alison

AU - Marder, Karen

AU - Fiske, Brian

AU - Sutherland, Margaret

AU - Xiromerisiou, Georgia

AU - Myers, Richard H.

AU - Clark, Lorraine N.

AU - Stefansson, Kari

AU - Hardy, John A.

AU - Heutink, Peter

AU - Chen, Honglei

AU - Wood, Nicholas W.

AU - Houlden, Henry

AU - Payami, Haydeh

AU - Brice, Alexis

AU - Scott, William K.

AU - Gasser, Thomas

AU - Bertram, Lars

AU - Eriksson, Nicholas

AU - Foroud, Tatiana

AU - Singleton, Andrew B.

AU - Plagnol, Vincent

AU - Sheerin, Una Marie

AU - Slevin, J.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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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JF - Nature Genetics

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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