LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease.
LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease.
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DOI：
10.1007/s10048-010-0241-x
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发表时间：
2010-10
期刊：
影响因子：
2.2
通讯作者：
Farrer, Matthew J.
中科院分区：
文献类型：
--
作者：
Vilarino-Gueell, Carles;Wider, Christian;Ross, Owen A.;Jasinska-Myga, Barbara;Kachergus, Jennifer;Cobb, Stephanie A.;Soto-Ortolaza, Alexandra I.;Behrouz, Bahareh;Heckman, Michael G.;Diehl, Nancy N.;Testa, Claudia M.;Wszolek, Zbigniew K.;Uitti, Ryan J.;Jankovic, Joseph;Louis, Elan D.;Clark, Lorraine N.;Rajput, Alex;Farrer, Matthew J.
富含亮氨酸重复序列和含有IG结构域的1基因（LINGO 1）的遗传变异最近与原发性震颤（ET）和帕金森病（PD）的风险增加相关。在此，我们通过对患者（ET，n=95; PD，n=96）的LINGO 1和LINGO 2基因进行测序，并通过检查多中心北美患者系列（ET，n= 1，247; PD，n=633）和对照组（n=642）的单倍型标记单核苷酸多态性（tSNP），对ET和PD进行了全面研究。测序研究在LINGO 1中鉴定出6种新的编码变体（p.S4C、p.V107M、p.A277T、p.R423R、p.G537A、p.D610D），在LINGO 2中鉴定出3种新的编码变体（p.D135D、p.P217P、p.V565V），但分离分析不支持致病性。该关联研究在LINGO 1位点使用了16个tSNP，在LINGO 2位点使用了21个tSNP。LINGO 1中的一个变体（rs 9652490）显示出与ET（比值比（OR）=0.63; P=0.026）和PD（OR=0.54; P=0.016）相关的证据。LINGO 1和LINGO 2中分别有4个和1个tSNP与ET相关，LINGO 2中有1个tSNP与PD相关（P<0.05）。进一步分析发现LINGO 1中的一个tSNP和LINGO 2中的两个tSNP影响ET发病时的年龄，LINGO 1中的两个tSNP改变PD发病时的年龄（P<0.05）。我们的研究结果支持LINGO 1和LINGO 2在确定ET和PD发病风险和发病年龄方面的作用。进一步的研究是必要的，以证实这些发现，并确定致病机制。
Genetic variation in the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) was recently associated with an increased risk of developing essential tremor (ET) and Parkinson disease (PD). Herein, we performed a comprehensive study of LINGO1 and its paralog LINGO2 in ET and PD by sequencing both genes in patients (ET, n=95; PD, n=96) and by examining haplotype-tagging single-nucleotide polymorphisms (tSNPs) in a multicenter North American series of patients (ET, n=1,247; PD, n=633) and controls (n=642). The sequencing study identified six novel coding variants in LINGO1 (p.S4C, p.V107M, p.A277T, p.R423R, p.G537A, p.D610D) and three in LINGO2 (p.D135D, p.P217P, p.V565V), however segregation analysis did not support pathogenicity. The association study employed 16 tSNPs at the LINGO1 locus and 21 at the LINGO2 locus. One variant in LINGO1 (rs9652490) displayed evidence of an association with ET (odds ratio (OR)=0.63; P=0.026) and PD (OR=0.54; P=0.016). Additionally, four other tSNPs in LINGO1 and one in LINGO2 were associated with ET and one tSNP in LINGO2 associated with PD (P<0.05). Further analysis identified one tSNP in LINGO1 and two in LINGO2 which influenced age at onset of ET and two tSNPs in LINGO1 which altered age at onset of PD (P<0.05). Our results support a role for LINGO1 and LINGO2 in determining risk for and perhaps age at onset of ET and PD. Further studies are warranted to confirm these findings and to determine the pathogenic mechanisms involved.
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