Genome-wide survey of copy number variants finds MAPT duplications in progressive supranuclear palsy
Genome-wide survey of copy number variants finds MAPT duplications in progressive supranuclear palsy
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DOI：
10.1002/mds.27702
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发表时间：
2019-07-01
影响因子：
8.6
通讯作者：
Al-Chalabi, Ammar
中科院分区：
文献类型：
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作者：
Chen, Zhongbo;Chen, Jason A.;Al-Chalabi, Ammar
背景进行性核上性瘫痪是一种神经退行性疾病，临床表现为进行性无运动-僵直综合征。在这项研究中，我们试图通过对一组特征良好的患者进行全基因组关联分析来确定影响PSP易感性的基因变异，这些患者参与了帕金森加综合征的神经保护和自然病史研究以及帕金森加综合征的血脑屏障研究。方法对来自英国、德国和法国的283例PSP患者进行单核苷酸多态基因分型，并与4472例对照进行比较。从基因分型数据中鉴定出拷贝数变异。结果我们在17号染色体上观察到MAPT基因内部或附近的关联，并探索了该基因的遗传结构。我们证实了先前报道的MOBP基因rs1768208(P=3.29×10(-13))和STX6基因rs1411478(P=3.45×10(-10))的关联。MAPT、MOBP和STX6单核苷酸多态的人群归因危险度分别为0.37、0.26和0.08。此外，我们在PSP患者中发现了2例跨越MAPT基因的拷贝数变异。这些拷贝数变异包括tau，但在17号染色体单倍型区域内几乎没有其他基因，这为PSP中MAPT的直接致病提供了额外的支持。结论临床医生还应意识到MAPT重复是PSP的一个可能的遗传原因，尤其是在发病年龄较小的患者中。(C)2019国际帕金森病和运动障碍学会
Background Progressive supranuclear palsy is a neurodegenerative tauopathy manifesting clinically as a progressive akinetic-rigid syndrome. In this study, we sought to identify genetic variants influencing PSP susceptibility through a genome-wide association analysis of a cohort of well-characterized patients who had participated in the Neuroprotection and Natural History in Parkinson Plus Syndromes and Blood Brain Barrier in Parkinson Plus Syndromes studies. Methods We genotyped single-nucleotide polymorphisms in 283 PSP cases from the United Kingdom, Germany, and France and compared these with genotypes from 4472 controls. Copy number variants were identified from genotyping data. Results We observed associations on chromosome 17 within or close to the MAPT gene and explored the genetic architecture at this locus. We confirmed the previously reported association of rs1768208 in the MOBP gene (P = 3.29 x 10(-13)) and rs1411478 in STX6 (P = 3.45 x 10(-10)). The population-attributable risk from the MAPT, MOBP, and STX6 single-nucleotide polymorphisms was found to be 0.37, 0.26, and 0.08, respectively. In addition, we found 2 instances of copy number variants spanning the MAPT gene in patients with PSP. These copy number variants include tau but few other genes within the chromosome 17 haplotype region, providing additional support for the direct pathogenicity of MAPT in PSP. Conclusions Clinicians should also be aware of MAPT duplication as a possible genetic cause of PSP, especially in patients presenting with young age at onset. (c) 2019 International Parkinson and Movement Disorder Society