title: A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease.
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.
authors.affiliation: Department of Psychological Medicine and Neurology, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre in Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.forename: Valentina
authors.initials: V
authors.lastname: Moskvina
authors.forename: Lesley
authors.initials: L
authors.lastname: Jones
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.forename: Alexey
authors.initials: A
authors.lastname: Vedernikov
authors.forename: Finja
authors.initials: F
authors.lastname: Buchel
authors.forename: Mohamad
authors.initials: M
authors.lastname: Saad
authors.forename: Mohamad
authors.initials: M
authors.lastname: Sadd
authors.forename: Jose M
authors.initials: JM
authors.lastname: Bras
authors.forename: Francesco
authors.initials: F
authors.lastname: Bettella
authors.forename: Nayia
authors.initials: N
authors.lastname: Nicolaou
authors.forename: Javier
authors.initials: J
authors.lastname: Simón-Sánchez
authors.forename: Florian
authors.initials: F
authors.lastname: Mittag
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.forename: Claudia
authors.initials: C
authors.lastname: Schulte
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefánsson
authors.forename: Kari
authors.initials: K
authors.lastname: Majamaa
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Huw R
authors.initials: HR
authors.lastname: Morris
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Williams
mesh_terms: D000483:Alleles; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics / Q000276:immunology; D010300:Parkinson Disease / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012306:Risk
chemical_list: D006680:HLA Antigens