PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease
PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease
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DOI：
10.1212/wnl.0000000000001332
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发表时间：
2015-03-10
期刊：
影响因子：
9.9
通讯作者：
Vance, Jeffery M.
中科院分区：
文献类型：
--
作者：
Beecham, Gary W.;Dickson, Dennis W.;Vance, Jeffery M.
目的：为了最大限度地减少帕金森病(PD)遗传学研究中的病理异质性，尸检证实的帕金森病遗传学联合会对符合神经病理诊断标准的484例帕金森病患者和1,145名对照进行了全基因组关联研究。方法：对符合神经病理诊断标准的484例患者和1,145名对照进行基因分型，然后输入3922,209个变异进行全基因组关联研究。结果：1号染色体上的一小段区域与帕金森病有很强的关联(rs10788972；p=6.23x10(-8))。关联峰位于之前定义PARK10基因座的2个正连锁研究的最大连锁峰内，并且非常接近。我们发现rs10788972与rs914722处于强连锁不平衡，单核苷酸多态定义PARK10单倍型与帕金森病的发病年龄显著相关。含有PARK10基因座的区域从10.6兆碱基显著减少到100千碱基，包含4个已知基因：TCEANC2、TMEM59、miR-4781和LDLRAD1。结论：我们证实PARK10单倍型与特发性帕金森病的发病风险有关。此外，我们显著减少了PARK10区域的大小。新的PARK10区域的候选基因中没有一个以前与帕金森病的生物学有关，这表明了新的潜在研究领域。这项研究强烈表明，减少病理异质性可能会加强遗传关联研究在帕金森病中的应用。
Objective: To minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls.Methods: Four hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis.Results: A small region on chromosome 1 was strongly associated with PD (rs10788972; p = 6.23 x 10(-8)). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1.Conclusions: We confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD.