Establishing the role of rare coding variants in known Parkinson's disease risk loci

NEUROBIOLOGY OF AGING

卷:59

Article

Jansen, Iris E.^1,2  Gibbs, J. Raphael³  Nalls, Mike A.^3,4  Price, T. Ryan⁵  Lubbe, Steven⁶  van Rooij, Jeroen⁷  Uitterlinden, Andre G.^7,8,9  Kraaij, Robert^8,9  Williams, Nigel M.¹⁰  Brice, Alexis^11,12  Hardy, John¹³  Wood, Nicholas W.¹⁴  Morris, Huw R.¹⁴  Gasser, Thomas¹⁵  Singleton, Andrew B.³  Heutink, Peter^2,15  Sharma, Manu¹⁵ 

[1] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands

[2] German Ctr Neurodegenerat Dis DZNE, Genome Biol Neurodegenerat Dis, Tubingen, Germany

[3] NIA, Lab Neurogenet, Bethesda, MD 20892 USA

[4] Data Tecn Int, Glen Echo, MD USA

[5] Univ Calif Irvine, Irvine, CA USA

[6] Northwestern Univ, Ken & Ruth Davee Dept Neurol, Feinberg Sch Med, Chicago, IL 60611 USA

[7] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[8] NCHA, Rotterdam, Netherlands

[9] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[10] Cardiff Univ, JMRC Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales

[11] UPMC Univ Paris 06, Sorbonne Univ, CNRS UMR7225, Inserm U1127,UMR S1127,Inst Cerveau & Moelle Epin, Paris, France

[12] Hop La Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, Paris, France

[13] UCL, Reta Lila Weston Inst, London, England

[14] UCL Inst Neurol, Dept Clin Neurosci, London, England

[15] Univ Tubingen, Inst Clin Epidemiol & Appl Biometry, Ctr Genet Epidemiol, Silcherstr 5, D-72072 Tubingen, Germany

关键词: Parkinson's disease;    Common risk loci;    Rare variants;    Whole exome sequencing;    Variant aggregation test;   

DOI  :  10.1016/j.neurobiolaging.2017.07.009

来源: Elsevier

【 摘 要 】

Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks. (C) 2017 Elsevier Inc. All rights reserved.

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