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Oxford University Press (OUP), Human Molecular Genetics, 2(23), p. 562-562

DOI: 10.1093/hmg/ddt554

Oxford University Press (OUP), Human Molecular Genetics, 5(22), p. 1039-1049

DOI: 10.1093/hmg/dds492

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A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease.

Journal article published in 2012 by Peter Holmans, B. P. C. van de Warrenburg, Nw W. Wood, Rob M. A. de Bie, Nm M. Williams, Karin D. van Dijk, Jacobus J. van Hilten, Bart van de Warrenburg, Daan Velseboer, Marie Vidailhet, Robert Walker, Mirdhu Wickremaratchi, Caroline H. Williams-Gray, Sophie Winder-Rhodes, Nicholas W. Wood and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people over 60 and 3-4% in people over 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<1x10(-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 regulation of leukocyte/lymphocyte activity and also cytokine 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.