A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci

被引：841

作者：

Chang, Diana ^{[1
]}

Nalls, Mike A. ^{[2
,3
]}

Hallgrimsdottir, Ingileif B. ^{[4
,5
]}

Hunkapiller, Julie ^{[1
]}

van der Brug, Marcel ^{[1
,6
]}

Cai, Fang ^{[1
]}

Kerchner, Geoffrey A. ^{[1
]}

Ayalon, Gai ^{[1
]}

Bingol, Baris ^{[1
]}

Sheng, Morgan ^{[1
]}

Hinds, David ^{[4
]}

Behrens, Timothy W. ^{[1
]}

Singleton, Andrew B. ^{[2
]}

Bhangale, Tushar R. ^{[1
]}

Graham, Robert R. ^{[1
]}

机构：

[1] Genentech Inc, San Francisco, CA 94080 USA

[2] NIA, Lab Neurogenet, US Natl Inst Hlth, Bethesda, MD 20892 USA

[3] Data Tecn Int, Glen Echo, MD USA

[4] 23&Me Inc, Mountain View, CA USA

[5] Amgen Inc, San Francisco, CA USA

[6] E Scape Bio, San Francisco, CA USA

来源：

NATURE GENETICS | 2017年 / 49卷 / 10期

关键词：

IMPUTATION; GENETICS; DATABASE; VARIANTS; TRANSCRIPTOME; HERITABILITY; ALZHEIMERS; CATHEPSINS; IMMUNITY; PROGRESS;

D O I：

10.1038/ng.3955

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Common variant genome-wide association studies (GWASs) have, to date, identified > 24 risk loci for Parkinson's disease (PD). To discover additional loci, we carried out a GWAS comparing 6,476 PD cases with 302,042 controls, followed by a meta-analysis with a recent study of over 13,000 PD cases and 95,000 controls at 9,830 overlapping variants. We then tested 35 loci (P < 1 x 10(-6)) in a replication cohort of 5,851 cases and 5,866 controls. We identified 17 novel risk loci (P < 5 x 10(-8)) in a joint analysis of 26,035 cases and 403,190 controls. We used a neurocentric strategy to assign candidate risk genes to the loci. We identified protein-altering or cis-expression quantitative trait locus (cis-eQTL) variants in linkage disequilibrium with the index variant in 29 of the 41 PD loci. These results indicate a key role for autophagy and lysosomal biology in PD risk, and suggest potential new drug targets for PD.

引用

页码：1511 / +

页数：8

共 65 条

[31] Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease [J].

Keller, Margaux F. ;

Saad, Mohamad ;

Bras, Jose ;

Bettella, Francesco ;

Nicolaou, Nayia ;

Simon-Sanchez, Javier ;

Mittag, Florian ;

Buechel, Finja ;

Sharma, Manu ;

Gibbs, J. Raphael ;

Schulte, Claudia ;

Moskvina, Valentina ;

Durr, Alexandra ;

Holmans, Peter ;

Kilarski, Laura L. ;

Guerreiro, Rita ;

Hernandez, Dena G. ;

Brice, Alexis ;

Ylikotila, Pauli ;

Stefansson, Hreinn ;

Majamaa, Kari ;

Morris, Huw R. ;

Williams, Nigel ;

Gasser, Thomas ;

Heutink, Peter ;

Wood, Nicholas W. ;

Hardy, John ;

Martinez, Maria ;

Singleton, Andrew B. ;

Nalls, Michael A. .

HUMAN MOLECULAR GENETICS, 2012, 21 (22) :4996-5009

[32] Integrating Functional Data to Prioritize Causal Variants in Statistical Fine-Mapping Studies [J].

Kichaev, Gleb ;

Yang, Wen-Yun ;

Lindstrom, Sara ;

Hormozdiari, Farhad ;

Eskin, Eleazar ;

Price, Alkes L. ;

Kraft, Peter ;

Pasaniuc, Bogdan .

PLOS GENETICS, 2014, 10 (10)

[33] Genetics of Parkinson's Disease [J].

Klein, Christine ;

Westenberger, Ana .

COLD SPRING HARBOR PERSPECTIVES IN MEDICINE, 2012, 2 (01)

[34] SATB1 Plays a Critical Role in Establishment of Immune Tolerance [J].

Kondo, Motonari ;

Tanaka, Yuriko ;

Kuwabara, Taku ;

Naito, Taku ;

Kohwi-Shigematsu, Terumi ;

Watanabe, Akiko .

JOURNAL OF IMMUNOLOGY, 2016, 196 (02) :563-572

[35] INRICH: interval-based enrichment analysis for genome-wide association studies [J].

Lee, Phil H. ;

O'Dushlaine, Colm ;

Thomas, Brett ;

Purcell, Shaun M. .

BIOINFORMATICS, 2012, 28 (13) :1797-1799

[36] Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood [J].

Lee, S. H. ;

Yang, J. ;

Goddard, M. E. ;

Visscher, P. M. ;

Wray, N. R. .

BIOINFORMATICS, 2012, 28 (19) :2540-2542

[37] Common variable immunodeficiency associated with microdeletion of chromosome 1q42.1-q42.3 and inositol 1,4,5-trisphosphate kinase B (ITPKB) deficiency [J].

Louis, Ankmalika G. ;

Yel, Leman ;

Cao, Jia N. ;

Agrawal, Sudhanshu ;

Gupta, Sudhir .

CLINICAL & TRANSLATIONAL IMMUNOLOGY, 2016, 5

[38] Bayesian refinement of association signals for 14 loci in 3 common diseases [J].

Maller, Julian B. ;

McVean, Gilean ;

Byrnes, Jake ;

Vukcevic, Damjan ;

Palin, Kimmo ;

Su, Zhan ;

Howson, Joanna M. M. ;

Auton, Adam ;

Myers, Simon ;

Morris, Andrew ;

Pirinen, Matti ;

Brown, Matthew A. ;

Burton, Paul R. ;

Caulfield, Mark J. ;

Compston, Alastair ;

Farrall, Martin ;

Hall, Alistair S. ;

Hattersley, Andrew T. ;

Hill, Adrian V. S. ;

Mathew, Christopher G. ;

Pembrey, Marcus ;

Satsangi, Jack ;

Stratton, Michael R. ;

Worthington, Jane ;

Craddock, Nick ;

Hurles, Matthew ;

Ouwehand, Willem ;

Parkes, Miles ;

Rahman, Nazneen ;

Duncanson, Audrey ;

Todd, John A. ;

Kwiatkowski, Dominic P. ;

Samani, Nilesh J. ;

Gough, Stephen C. L. ;

McCarthy, Mark I. ;

Deloukas, Panagiotis ;

Donnelly, Peter .

NATURE GENETICS, 2012, 44 (12) :1294-1301

[39] Cysteine cathepsins are essential in lysosomal degradation of α-synuclein [J].

McGlinchey, Ryan P. ;

Lee, Jennifer C. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2015, 112 (30) :9322-9327

[40] Mendelian inheritance in man and its online version, OMIM [J].

McKusick, Victor A. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 80 (04) :588-604

← 1 2 3 4 5 6 7 →