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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.

SUBMITTER: Holmans P

PROVIDER: S-EPMC3561909 | biostudies-other | 2013 Mar

REPOSITORIES: biostudies-other

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

Holmans Peter P Moskvina Valentina V Jones Lesley L Sharma Manu M Vedernikov Alexey A Buchel Finja F Saad Mohamad M Bras Jose M JM Bettella Francesco F Nicolaou Nayia N Simón-Sánchez Javier J Mittag Florian F Gibbs J Raphael JR Schulte Claudia C Durr Alexandra A Guerreiro Rita R Hernandez Dena D Brice Alexis A Stefánsson Hreinn H Majamaa Kari K Gasser Thomas T Heutink Peter P Wood Nicholas W NW Martinez Maria M Singleton Andrew B AB Nalls Michael A MA Hardy John J Morris Huw R HR Williams Nigel M NM

Human molecular genetics 20121207 5

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 prev ...[more]

PMID: 23223016

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Project description:Dopaminergic pathway is the most disrupted pathway in the pathogenesis of Parkinson's disease. Several studies reported associations of dopaminergic genes with the occurrence of adverse events of dopaminergic treatment. However, none of these studies adopted a pathway based approach. The aim of this study was to comprehensively evaluate the influence of selected single nucleotide polymorphisms of key dopaminergic pathway genes on the occurrence of motor and non-motor adverse events of dopaminergic treatment in Parkinson's disease. In total, 231 Parkinson's disease patients were enrolled. Demographic and clinical data were collected. Genotyping was performed for 16 single nucleotide polymorphisms from key dopaminergic pathway genes. Logistic and Cox regression analyses were used for evaluation. Results were adjusted for significant clinical data. We observed that carriers of at least one COMT rs165815 C allele had lower odds for developing visual hallucinations (OR = 0.34; 95% CI = 0.16-0.72; p = 0.004), while carriers of at least one DRD3 rs6280 C allele and CC homozygotes had higher odds for this adverse event (OR = 1.88; 95% CI = 1.00-3.54; p = 0.049 and OR = 3.31; 95% CI = 1.37-8.03; p = 0.008, respectively). Carriers of at least one DDC rs921451 C allele and CT heterozygotes had higher odds for orthostatic hypotension (OR = 1.86; 95% CI = 1.07-3.23; p = 0.028 and OR = 2.30; 95% CI = 1.26-4.20; p = 0.007, respectively). Heterozygotes for DDC rs3837091 and SLC22A1 rs628031 AA carriers also had higher odds for orthostatic hypotension (OR = 1.94; 95% CI = 1.07-3.51; p = 0.028 and OR = 2.57; 95% CI = 1.11-5.95; p = 0.028, respectively). Carriers of the SLC22A1 rs628031 AA genotype had higher odds for peripheral edema and impulse control disorders (OR = 4.00; 95% CI = 1.62-9.88; p = 0.003 and OR = 3.16; 95% CI = 1.03-9.72; p = 0.045, respectively). Finally, heterozygotes for SLC22A1 rs628031 and carriers of at least one SLC22A1 rs628031 A allele had lower odds for dyskinesia (OR = 0.48; 95% CI = 0.24-0.98, p = 0.043 and OR = 0.48; 95% CI = 0.25-0.92; p = 0.027, respectively). Gene-gene interactions, more specifically DDC-COMT, SLC18A2-SV2C, and SLC18A2-SLC6A3, also significantly influenced the occurrence of some adverse events. Additionally, haplotypes of COMT and SLC6A3 were associated with the occurrence of visual hallucinations (AT vs. GC: OR = 0.34; 95% CI = 0.16-0.72; p = 0.005) and orthostatic hypotension (ATG vs. ACG: OR = 2.48; 95% CI: 1.01-6.07; p = 0.047), respectively. Pathway based approach allowed us to identify new potential candidates for predictive biomarkers of adverse events of dopaminergic treatment in Parkinson's disease, which could contribute to treatment personalization.

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

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

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