Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease.
Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease.
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DOI：
10.1186/s13024-016-0097-0
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发表时间：
2016-04-19
影响因子：
15.1
通讯作者：
Cruchaga C
中科院分区：
文献类型：
--
作者：
Benitez BA;Davis AA;Jin SC;Ibanez L;Ortega-Cubero S;Pastor P;Choi J;Cooper B;Perlmutter JS;Cruchaga C
大多数帕金森病（PD）的测序研究主要集中在家族性和早发性PD样本中的特定基因上，或者集中在散发性PD病例中筛选单一变异。迄今为止，还没有系统的研究对具有孟德尔遗传的最常见的PD引起基因[α-突触核蛋白（SNCA）、富含亮氨酸的重复激酶2（LRRK 2）、PARKIN、PTEN诱导的推定激酶1（PINK 1）和DJ-1（Daisuke-Junko-1）]和通过全基因组关联研究鉴定的易感基因[葡萄糖脑苷脂酶β酸（GBA）和微管相关蛋白tau（MAPT）]（GWAS）在欧美病例对照样本（n=815）。在2%的PD患者中发现SNCA、LRRK 2和PARK 2基因的致病变异。LRRK 2，p.G2019S突变在散发性PD和家族性PD中的检出率分别为0.6%和4.8%。基于基因的分析表明，LRRK 2基因中的其他变异也会导致PD风险。0.8%的家族性PD患者存在SNCA重复。在0.8%的PD病例和0.6%的对照中发现了新的变异。在7.1%的PD患者中发现GBA基因中的杂合戈谢病致病突变。在这里，我们确定GBA变体（p.T408M）与PD风险和发病年龄相关。此外，基于基因和单变异体的分析表明，GBA基因变异体（p.L483P、p.R83C、p.N409S、p.H294Q和p.E365K）增加PD风险。我们的数据表明，GBA和LRRK 2基因中其他未经测试的编码变体的影响高于先前的估计。我们的数据还提供了令人信服的证据，证明在原发性孟德尔和PD GWAS基因中存在其他未经测试的变异，这些变异有助于散发性PD的遗传病因学。
Most sequencing studies in Parkinson’s disease (PD) have focused on either a particular gene, primarily in familial and early onset PD samples, or on screening single variants in sporadic PD cases. To date, there is no systematic study that sequences the most common PD causing genes with Mendelian inheritance [α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), PARKIN, PTEN-induced putative kinase 1 (PINK1) and DJ-1 (Daisuke-Junko-1)] and susceptibility genes [glucocerebrosidase beta acid (GBA) and microtubule-associated protein tau (MAPT)] identified through genome-wide association studies (GWAS) in a European-American case-control sample (n=815). Disease-causing variants in the SNCA,LRRK2 and PARK2 genes were found in 2 % of PD patients. The LRRK2, p.G2019S mutation was found in 0.6 % of sporadic PD and 4.8 % of familial PD cases. Gene-based analysis suggests that additional variants in the LRRK2 gene also contribute to PD risk. The SNCA duplication was found in 0.8 % of familial PD patients. Novel variants were found in 0.8 % of PD cases and 0.6 % of controls. Heterozygous Gaucher disease-causing mutations in the GBA gene were found in 7.1 % of PD patients. Here, we established that the GBA variant (p.T408M) is associated with PD risk and age at onset. Additionally, gene-based and single-variant analyses demostrated that GBA gene variants (p.L483P, p.R83C, p.N409S, p.H294Q and p.E365K) increase PD risk. Our data suggest that the impact of additional untested coding variants in the GBA and LRRK2 genes is higher than previously estimated. Our data also provide compelling evidence of the existence of additional untested variants in the primary Mendelian and PD GWAS genes that contribute to the genetic etiology of sporadic PD.