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

Mike A Nalls; Nathan Pankratz; Christina M Lill; Chuong B Do; Dena G Hernandez; Mohamad Saad; Anita L DeStefano; Eleanna Kara; Jose Bras; Manu Sharma; Claudia Schulte; Margaux F Keller; Sampath Arepalli; Christopher Letson; Connor Edsall; Hreinn Stefansson; Xinmin Liu; Hannah Pliner; Joseph H Lee; Rong Cheng; M Arfan Ikram; John P A Ioannidis; Georgios M Hadjigeorgiou; Joshua C Bis; Maria Martinez; Joel S Perlmutter; Alison Goate; Karen Marder; Brian Fiske; Margaret Sutherland; Georgia Xiromerisiou; Richard H Myers; Lorraine N Clark; Kari Stefansson; John A Hardy; Peter Heutink; Honglei Chen; Nicholas W Wood; Henry Houlden; Haydeh Payami; Alexis Brice; William K Scott; Thomas Gasser; Lars Bertram; Nicholas Eriksson; Tatiana Foroud; Andrew B Singleton; International Parkinson's Disease Genomics Consortium (IPDGC); Karen Morrison

doi:10.1038/ng.3043

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

Mike A Nalls, Nathan Pankratz, Christina M Lill, Chuong B Do, Dena G Hernandez, Mohamad Saad, Anita L DeStefano, Eleanna Kara, Jose Bras, Manu Sharma, Claudia Schulte, Margaux F Keller, Sampath Arepalli, Christopher Letson, Connor Edsall, Hreinn Stefansson, Xinmin Liu, Hannah Pliner, Joseph H Lee, Rong ChengM Arfan Ikram, John P A Ioannidis, Georgios M Hadjigeorgiou, Joshua C Bis, Maria Martinez, Joel S Perlmutter, Alison Goate, Karen Marder, Brian Fiske, Margaret Sutherland, Georgia Xiromerisiou, Richard H Myers, Lorraine N Clark, Kari Stefansson, John A Hardy, Peter Heutink, Honglei Chen, Nicholas W Wood, Henry Houlden, Haydeh Payami, Alexis Brice, William K Scott, Thomas Gasser, Lars Bertram, Nicholas Eriksson, Tatiana Foroud, Andrew B Singleton, International Parkinson's Disease Genomics Consortium (IPDGC), Karen Morrison

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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)	989-93
Number of pages	5
Journal	Nature Genetics
Volume	46
Issue number	9
DOIs	https://doi.org/10.1038/ng.3043
Publication status	Published - Sept 2014

Keywords

Case-Control Studies
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Parkinson Disease
Polymorphism, Single Nucleotide
Risk Factors

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Nalls, M. A., Pankratz, N., Lill, C. M., Do, C. B., Hernandez, D. G., Saad, M., DeStefano, A. L., Kara, E., Bras, J., Sharma, M., Schulte, C., Keller, M. F., Arepalli, S., Letson, C., Edsall, C., Stefansson, H., Liu, X., Pliner, H., Lee, J. H., ... Morrison, K. (2014). Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nature Genetics, 46(9), 989-93. https://doi.org/10.1038/ng.3043

@article{782c1884f7ee4dcf90f9ae61cd3e383e,

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.",

keywords = "Case-Control Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Parkinson Disease, Polymorphism, Single Nucleotide, Risk Factors",

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 {International Parkinson's Disease Genomics Consortium (IPDGC)} and Karen Morrison",

year = "2014",

month = sep,

doi = "10.1038/ng.3043",

language = "English",

volume = "46",

pages = "989--93",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

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Nalls, MA, Pankratz, N, Lill, CM, Do, CB, Hernandez, DG, Saad, M, DeStefano, AL, Kara, E, Bras, J, Sharma, M, Schulte, C, Keller, MF, Arepalli, S, Letson, C, Edsall, C, Stefansson, H, Liu, X, Pliner, H, Lee, JH, Cheng, R, Ikram, MA, Ioannidis, JPA, Hadjigeorgiou, GM, Bis, JC, Martinez, M, Perlmutter, JS, Goate, A, Marder, K, Fiske, B, Sutherland, M, Xiromerisiou, G, Myers, RH, Clark, LN, Stefansson, K, Hardy, JA, Heutink, P, Chen, H, Wood, NW, Houlden, H, Payami, H, Brice, A, Scott, WK, Gasser, T, Bertram, L, Eriksson, N, Foroud, T, Singleton, AB, International Parkinson's Disease Genomics Consortium (IPDGC) & Morrison, K 2014, 'Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease', Nature Genetics, vol. 46, no. 9, pp. 989-93. https://doi.org/10.1038/ng.3043

TY - JOUR

T1 - Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

AU - Nalls, Mike A

AU - Pankratz, Nathan

AU - Lill, Christina M

AU - Do, Chuong B

AU - Hernandez, Dena G

AU - Saad, Mohamad

AU - DeStefano, Anita L

AU - Kara, Eleanna

AU - Bras, Jose

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 - International Parkinson's Disease Genomics Consortium (IPDGC)

AU - Morrison, Karen

PY - 2014/9

Y1 - 2014/9

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.

KW - Case-Control Studies

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Parkinson Disease

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

U2 - 10.1038/ng.3043

DO - 10.1038/ng.3043

M3 - Article

C2 - 25064009

SN - 1061-4036

VL - 46

SP - 989

EP - 993

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

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

Abstract

Keywords

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