Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease
Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease
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DOI：
10.1002/mds.28037
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发表时间：
2020-07-01
影响因子：
8.6
通讯作者：
Kuhlenbaeumer, Gregor
中科院分区：
文献类型：
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作者：
Hopfner, Franziska;Mueller, Stefanie H.;Kuhlenbaeumer, Gregor
目的帕金森病（PD）患者体内α-突触核蛋白等细胞成分的溶酶体降解障碍可能在PD发病中起重要作用。葡萄糖脑苷脂酶（GBA）基因的罕见遗传变异与PD一致相关。在这里，我们研究溶酶体候选基因的罕见变异与PD之间的关联。方法我们使用合并的靶向下一代DNA测序技术，研究了4096例PD患者和同等数量的对照组中23个溶酶体候选基因中PD与罕见遗传变异之间的相关性。病例或对照中罕见变异的基因关联使用优化的序列核关联检验与23个测试基因的Bonferroni校正进行分析。结果我们证实了GBA中罕见变异与PD的相关性，并报道了ATP 13 A2、LAMP 1、TMEM 175和VPS 13 C中罕见变异的新相关性。结论PD与溶酶体基因的罕见变异有关，GBA是最早的突变。在全基因组关联研究中，先前与单基因PD相关的ATP 13 A2和VPC 13 C中的罕见变异以及先前与散发性PD相关的TMEM 175和VPS 13 C中的更常见变异与PD相关。(c)2020国际帕金森和运动障碍协会
Objective Impaired lysosomal degradation of alpha-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. Methods We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. Results We confirm the association of rare variants inGBAwith PD and report novel associations for rare variants inATP13A2,LAMP1,TMEM175, andVPS13C. Conclusion Rare variants in selected lysosomal genes, first and foremostGBA, are associated with PD. Rare variants inATP13A2andVPC13Cpreviously linked to monogenic PD and more common variants inTMEM175andVPS13Cpreviously linked to sporadic PD in genome-wide association studies are associated with PD. (c) 2020 International Parkinson and Movement Disorder Society