Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease.
Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease.
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DOI：
10.1001/jamaneurol.2018.1885
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发表时间：
2018-11-01
期刊：
影响因子：
29
通讯作者：
COURAGE-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson’s Disease) Consortium, the French Parkinson’s Disease Consortium, and the International Parkinson’s Disease Genomics Consortium (IPDGC)
中科院分区：
文献类型：
--
作者：
Blauwendraat C;Reed X;Kia DA;Gan-Or Z;Lesage S;Pihlstrøm L;Guerreiro R;Gibbs JR;Sabir M;Ahmed S;Ding J;Alcalay RN;Hassin-Baer S;Pittman AM;Brooks J;Edsall C;Hernandez DG;Chung SJ;Goldwurm S;Toft M;Schulte C;Bras J;Wood NW;Brice A;Morris HR;Scholz SW;Nalls MA;Singleton AB;Cookson MR;COURAGE-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson’s Disease) Consortium, the French Parkinson’s Disease Consortium, and the International Parkinson’s Disease Genomics Consortium (IPDGC)
LRRK 2的致病性变体是帕金森病（PD）的相对常见的遗传原因。目前，疾病的分子机制尚不清楚，并假定了发病机制的功能获得和丧失（LOF）模型。据报道，LRRK 2变体导致底物磷酸化增强和细胞死亡增加。然而，Lrrk 2及其同源物Lrrk 1的双敲除导致小鼠模型中的神经变性，表明疾病可能通过LOF发生。由于LRRK 2抑制剂目前正在开发作为PD的潜在疾病修饰治疗，因此确定LRRK 2中的LOF变体是否增加或降低PD的风险至关重要。确定LRRK 1和LRRK 2 LOF变异体是否有助于发生PD的风险。为了确定LRRK 2介导的疾病在人群中的流行机制，分析了来自大型病例对照队列（> 23000人）的下一代测序数据中LRRK 1和LRRK 2的LOF变体。在5个不同的研究中心和5个不同的数据集生成数据，包括临床诊断为PD的病例和神经学正常的对照个体。数据收集自2012年至2017年。LRRK 1和LRRK 2 LOF变异体在一般人群中的频率以及病例和对照之间的比较。在11095例PD患者和12615例对照中，LRRK 1 LOF变异的检出率分别为0.205%和0.139（比值比，1.48;标准差，0.571; 95%可信区间，0.45-4.44;在0.117%的病例和0.087%的对照中发现了LRRK 2 LOF变异（比值比，1.48; SE，0.431; 95%CI，0.63-3.50; P = 0.36）。所有相关性检验均表明LRRK 1或LRRK 2变异体与PD之间缺乏相关性。对来自几种杂合LOF变体携带者的淋巴母细胞系的进一步分析发现，与野生型等位基因相比，LRRK 2蛋白水平降低了约一半。总之，这些发现表明LRRK 1或LRRK 2的单倍不足既不是PD的原因，也不是PD的保护作用。此外，这些结果表明，激酶抑制或等位基因特异性靶向突变LRRK 2仍然是可行的治疗策略在PD。
Pathogenic variants in LRRK2 are a relatively common genetic cause of Parkinson disease (PD). Currently, the molecular mechanism underlying disease is unknown, and gain and loss of function (LOF) models of pathogenesis have been postulated. LRRK2 variants are reported to result in enhanced phosphorylation of substrates and increased cell death. However, the double knockout of Lrrk2 and its homologue Lrrk1 results in neurodegeneration in a mouse model, suggesting that disease may occur by LOF. Because LRRK2 inhibitors are currently in development as potential disease-modifying treatments in PD, it is critical to determine whether LOF variants in LRRK2 increase or decrease the risk of PD. To determine whether LRRK1 and LRRK2 LOF variants contribute to the risk of developing PD. To determine the prevailing mechanism of LRRK2-mediated disease in human populations, next-generation sequencing data from a large case-control cohort (>23 000 individuals) was analyzed for LOF variants in LRRK1 and LRRK2. Data were generated at 5 different sites and 5 different data sets, including cases with clinically diagnosed PD and neurologically normal control individuals. Data were collected from 2012 through 2017. Frequencies of LRRK1 and LRRK2 LOF variants present in the general population and compared between cases and controls. Among 11 095 cases with PD and 12 615 controls, LRRK1 LOF variants were identified in 0.205% of cases and 0.139% of controls (odds ratio, 1.48; SE, 0.571; 95% CI, 0.45-4.44; P = .49) and LRRK2 LOF variants were found in 0.117% of cases and 0.087% of controls (odds ratio, 1.48; SE, 0.431; 95% CI, 0.63-3.50; P = .36). All association tests suggested lack of association between LRRK1 or LRRK2 variants and PD. Further analysis of lymphoblastoid cell lines from several heterozygous LOF variant carriers found that, as expected, LRRK2 protein levels are reduced by approximately half compared with wild-type alleles. Together these findings indicate that haploinsufficiency of LRRK1 or LRRK2 is neither a cause of nor protective against PD. Furthermore, these results suggest that kinase inhibition or allele-specific targeting of mutant LRRK2 remain viable therapeutic strategies in PD.
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影响因子：
16.2
作者：
Singleton A;Hardy J
通讯作者：
Hardy J
影响因子：
16.2
作者：
Giaime E;Tong Y;Wagner LK;Yuan Y;Huang G;Shen J
通讯作者：
Shen J
影响因子：
4.2
作者：
Blauwendraat C;Kia DA;Pihlstrøm L;Gan-Or Z;Lesage S;Gibbs JR;Ding J;Alcalay RN;Hassin-Baer S;Pittman AM;Brooks J;Edsall C;Chung SJ;Goldwurm S;Toft M;Schulte C;International Parkinson's Disease Genomics Consortium (IPDGC), COURAGE-PD Consortium;Hernandez D;Singleton AB;Nalls MA;Brice A;Scholz SW;Wood NW
通讯作者：
Wood NW
DOI：
10.1093/bioinformatics/btw079
发表时间：
2016-05-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Zhan X;Hu Y;Li B;Abecasis GR;Liu DJ
通讯作者：
Liu DJ
影响因子：
6.1
作者：
Greggio, Elisa;Jain, Shushant;Cookson, Mark R.
通讯作者：
Cookson, Mark R.