A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinsons disease
A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinsons disease
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DOI：
10.1093/hmg/dds492
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发表时间：
2013-03-01
影响因子：
3.5
通讯作者：
Williams, Nigel M.
中科院分区：
文献类型：
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作者：
Holmans, Peter;Moskvina, Valentina;Williams, Nigel M.
帕金森氏病(PD)是第二种最常见的神经退行性疾病，60岁的人中有12人患病，80岁的人中有34人患病。全基因组关联(GWA)研究现在已暗示至少18个基因组区域存在关联的重要证据。我们研究了一项大规模的PD-Meta分析，发现了与PD相关但低于全基因组显着性阈值的大量SNPs(P110(16))。这一结果与先前涉及的18个区域的变异无关，并暗示存在额外的多基因风险等位基因。为了了解这些基因座如何增加帕金森氏病的风险，我们应用了基于途径的分析，测试生物功能，这些功能显著丰富了包含与帕金森氏病相关的变异的基因。分析两个独立的GWA研究，我们发现这两个研究都在PD相关基因丰富的功能类别数量上存在显著过剩(最低分别为P 0.014和P 0.006)。此外，在这两项研究中，58个类别的相关基因显著丰富(P 0.001)，表明参与白细胞/淋巴细胞活动调节和细胞因子介导的信号传递的基因可能增加帕金森病的易感性。这些结果不会因为排除了所有178个基因而改变，这些基因存在于之前报道的与帕金森病强烈相关的18个基因组区域(包括人类白细胞抗原基因座)。因此，我们的发现为人类白细胞抗原基因座上的强关联信号提供了独立的支持，并暗示免疫相关的遗传易感性在基因组中可能比以前认识到的更广泛。
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.