A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinsons disease

被引：100

作者：

Holmans, Peter ^{[1
]}

Moskvina, Valentina ^{[1
]}

Jones, Lesley ^{[1
]}

Sharma, Manu ^{[4
,10
]}

Vedernikov, Alexey ^{[1
]}

Buchel, Finja ^{[3
]}

Sadd, Mohamad ^{[5
]}

Bras, Jose M. ^{[6
]}

Bettella, Francesco ^{[8
]}

Nicolaou, Nayia ^{[9
]}

Simon-Sanchez, Javier ^{[9
]}

Mittag, Florian ^{[3
]}

Gibbs, J. Raphael ^{[2
,6
]}

Schulte, Claudia ^{[4
,10
]}

Durr, Alexandra ^{[11
,12
]}

Guerreiro, Rita ^{[6
]}

Hernandez, Dena ^{[2
,6
]}

Brice, Alexis ^{[11
,12
,13
,14
]}

Stefansson, Hreinn ^{[8
]}

Majamaa, Kari ^{[15
]}

Gasser, Thomas ^{[4
,10
]}

Heutink, Peter ^{[9
]}

Wood, Nicholas W. ^{[6
,7
]}

Martinez, Maria ^{[5
]}

Singleton, Andrew B. ^{[2
]}

Nalls, Michael A. ^{[2
]}

Hardy, John ^{[6
]}

Morris, Huw R. ^{[1
]}

Williams, Nigel M. ^{[1
]}

机构：

[1] Cardiff Univ, Dept Psychol Med & Neurol, Inst Psychol Med & Clin Neurosci, MRC,Ctr Neuropsychiat Genet & Genom,Sch Med, Cardiff CF14 4XN, S Glam, Wales

[2] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[3] Univ Tubingen, Ctr Bioinformat Tuebingen ZBIT, Tubingen, Germany

[4] Univ Tubingen, Dept Neurodegenerat Dis, Hertie Inst Clin Brain Res, Tubingen, Germany

[5] Univ Toulouse 3, F-31062 Toulouse, France

[6] UCL, Inst Neurol, Dept Mol Neurosci, London, England

[7] UCL, UCL Genet Inst, London, England

[8] DeCODE Genet, Sci Serv, IS-101 Reykjavik, Iceland

[9] Vrije Univ Amsterdam Med Ctr, Sect Med Genom, Dept Clin Genet, Amsterdam, Netherlands

[10] German Ctr Neurodegenerat Dis, DZNE Deutsch Zentrum Neurodegenerat Erkrangungen, Tubingen, Germany

[11] Univ Paris 06, INSERM, CRICM, UMRS975,CNRS UMR 7225, F-75013 Paris, France

[12] Univ Paris 06, UMRS975, F-75013 Paris, France

[13] Hop La Pitie Salpetriere, AP HP, Dept Genet, Paris, France

[14] Inst Cerveau & Moelle Epiniere, F-75013 Paris, France

[15] Univ Oulu, Dept Med Biochem & Mol Biol, FIN-90014 Oulu, Finland

来源：

HUMAN MOLECULAR GENETICS | 2013年 / 22卷 / 05期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; ALPHA-SYNUCLEIN; RISK-FACTORS; PROTEIN; MUTATIONS; LIGASE; PINK1; VARIANTS; DATABASE; REGION;

D O I：

10.1093/hmg/dds492

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Parkinsons disease (PD) is the second most common neurodegenerative disease affecting 12 in people 60 and 34 in people 80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P 1 10(16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P 0.014 and P 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P 0.001), implicating genes involved in the oregulation of leucocyte/lymphocyte activity' and also ocytokine-mediated signalling' as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.

引用

页码：1039 / 1049

页数：11

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