The University of Southampton
University of Southampton Institutional Repository

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

A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease
A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease
Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1–2% in people >60 and 3–4% 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 ‘regulation of leucocyte/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.
1039-1049
Holmans, P.
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Moskvina, V.
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Jones, L.
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Sharma, M.
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Vedernikov, A.
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Buchel, F.
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Sadd, M.
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Bras, J.M.
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Bettella, F.
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Nicolaou, N.
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Simon-Sanchez, J.
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Mittag, F.
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Gibbs, J.R.
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Schulte, C.
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Durr, A.
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Guerreiro, R.
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Hernandez, D.
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Brice, A.
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Stefansson, H.
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Majamaa, K.
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Gasser, T.
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Heutink, P.
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Wood, N.W.
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Martinez, M.
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Singleton, A.B.
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Nalls, M. A.
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Hardy, J.
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Morris, H.R.
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Williams, N.M.
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Arepalli, S.
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Barker, R.
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Barrett, J.
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Ben-Shlomo, Y.
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Berg, D.
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Bhatia, K.
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de Bie, R.M.A.
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Biffi, A.
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Bloem, B.
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Bochdanovits, Z.
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Bonin, M.
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Brockmann, K.
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Brooks, J.
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Burn, D.J.
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Charlesworth, G.
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Chen, H.
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Chinnery, P. F.
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Chong, S.
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Clarke, C. E.
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Cookson, M.R.
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Corvol, J.-C.
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Counsell, C.
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Damier, P.
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Deloukas, P.
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Deuschl, G.
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van Dijk, K.D.
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Edkins, S.
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Evans, J.R.
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Gardner, M.
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Gray, E.
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Gustafsson, O.
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Harris, C.
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Hernandez, D.G.
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van Hilten, J.J.
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Hofman, A.
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Hollenbeck, A.
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Holton, J.
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Huber, H.
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Hudson, G.
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Hunt, S.E.
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Huttenlocher, J.
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Illig, T.
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Langford, C.
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Lees, A.
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Lesage, S.
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Lichtner, P.
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Limousin, P.
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Lopez, G.
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Lorenz, D.
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Moore, M.
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Morris, H.
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Morrison, K.E.
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Nalls, M.A.
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Pearson, J.
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Petursson, H.
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Plagnol, V.
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Pollak, P.
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Post, B.
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Potter, S.
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Ravina, B.
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Shaw, K.
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Smith, C.
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Holmans, P., Moskvina, V. and Jones, L. et al. (2013) A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease. Human Molecular Genetics, 22 (5), 1039-1049. (doi:10.1093/hmg/dds492). (PMID:23223016)

Record type: Article

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1–2% in people >60 and 3–4% 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 ‘regulation of leucocyte/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.

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Accepted/In Press date: 16 November 2012
e-pub ahead of print date: 7 December 2012
Published date: March 2013
Organisations: Medical Education

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Local EPrints ID: 398464
URI: http://eprints.soton.ac.uk/id/eprint/398464
PURE UUID: 69274812-fda5-45aa-8c07-3f126229dc2d
ORCID for K.E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 25 Jul 2016 14:03
Last modified: 17 Dec 2019 01:32

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Author: P. Holmans
Author: V. Moskvina
Author: L. Jones
Author: M. Sharma
Author: A. Vedernikov
Author: F. Buchel
Author: M. Sadd
Author: J.M. Bras
Author: F. Bettella
Author: N. Nicolaou
Author: J. Simon-Sanchez
Author: F. Mittag
Author: J.R. Gibbs
Author: C. Schulte
Author: A. Durr
Author: R. Guerreiro
Author: D. Hernandez
Author: A. Brice
Author: H. Stefansson
Author: K. Majamaa
Author: T. Gasser
Author: P. Heutink
Author: N.W. Wood
Author: M. Martinez
Author: A.B. Singleton
Author: M. A. Nalls
Author: J. Hardy
Author: H.R. Morris
Author: N.M. Williams
Author: S. Arepalli
Author: R. Barker
Author: J. Barrett
Author: Y. Ben-Shlomo
Author: H.W. Berendse
Author: D. Berg
Author: K. Bhatia
Author: R.M.A. de Bie
Author: A. Biffi
Author: B. Bloem
Author: Z. Bochdanovits
Author: M. Bonin
Author: K. Brockmann
Author: J. Brooks
Author: D.J. Burn
Author: G. Charlesworth
Author: H. Chen
Author: P. F. Chinnery
Author: S. Chong
Author: C. E. Clarke
Author: M.R. Cookson
Author: J.M. Cooper
Author: J.-C. Corvol
Author: C. Counsell
Author: P. Damier
Author: J.F. Dartigues
Author: P. Deloukas
Author: G. Deuschl
Author: D.T. Dexter
Author: K.D. van Dijk
Author: A. Dillman
Author: F. Durif
Author: S. Edkins
Author: J.R. Evans
Author: T. Foltynie
Author: J. Gao
Author: M. Gardner
Author: A. Goate
Author: E. Gray
Author: O. Gustafsson
Author: C. Harris
Author: D.G. Hernandez
Author: J.J. van Hilten
Author: A. Hofman
Author: A. Hollenbeck
Author: J. Holton
Author: M. Hu
Author: H. Huber
Author: G. Hudson
Author: S.E. Hunt
Author: J. Huttenlocher
Author: T. Illig
Author: C. Langford
Author: A. Lees
Author: S. Lesage
Author: P. Lichtner
Author: P. Limousin
Author: G. Lopez
Author: D. Lorenz
Author: A. McNeill
Author: C. Moorby
Author: M. Moore
Author: H. Morris
Author: K.E. Morrison ORCID iD
Author: E. Mudanohwo
Author: M.A. Nalls
Author: J. Pearson
Author: J.S. Perlmutter
Author: H. Petursson
Author: V. Plagnol
Author: P. Pollak
Author: B. Post
Author: S. Potter
Author: B. Ravina
Author: T. Revesz
Author: O. Riess
Author: F. Rivadeneira
Author: P. Rizzu
Author: M. Ryten
Author: M. Saad
Author: S. Sawcer
Author: A. Schapira
Author: H. Scheffer
Author: K. Shaw
Author: U.-M. Sheerin
Author: I. Shoulson
Author: E. Sidransky
Author: C. Smith
Author: K. Stefansson
Author: S. Steinberg
Author: J.D. Stockton
Author: S. Sveinbjornsdottir
Author: K. Talbot
Author: C.M. Tanner
Author: A. Tashakkori-Ghanbaria
Author: F. Tison
Author: D. Trabzuni
Author: B.J. Traynor
Author: A.G. Uitterlinden
Author: D. Velseboer
Author: M. Vidailhet
Author: R. Walker
Author: B. van de Warrenburg
Author: M. Wickremaratchi
Author: N. Williams
Author: C.H. Williams-Gray
Author: S. Winder-Rhodes
Author: N. Wood

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