Genomewide association analysis of human narcolepsy and a new resistance gene
Genomewide association analysis of human narcolepsy and a new resistance gene
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DOI：
10.1086/505539
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发表时间：
2006-08-01
影响因子：
9.8
通讯作者：
Tokunaga, Katsushi
中科院分区：
文献类型：
--
作者：
Kawashima, Minae;Tamiya, Gen;Tokunaga, Katsushi
人类嗜睡症是一种受多种遗传和环境因素影响的嗜睡症。与发作性睡病密切相关的一个遗传因素是6号染色体上人类白细胞抗原区域的HLA-DRB 1 *1501-DQB 1 *0602单倍型，而其他遗传因素尚不清楚。为了发现人类嗜睡症易感性或抗性的其他候选区域，我们使用23，244个微卫星标记进行了全基因组关联研究。两轮筛选与使用合并的DNA产生96个微卫星标记（包括16个标记的染色体6）与显着不同的估计频率的情况下，对照池。通过对95例病例和95例对照的个体分型，对不位于6号染色体上的标记物进行了评估; 30个标记物仍显示出显著的相关性。21号染色体上的一个标记（21q22.3）显示了很强的关联。周围区域进行高密度关联映射与14个额外的微卫星标记和74个SNP。一个微卫星标记（D21 S 0012 m）和两个SNPs（rs 13048981和rs 13046884）显示出强相关性（P <0.0005，比值比0.19 - 0.33）。这些多态性处于强烈的连锁不平衡中，并且该区域没有其他多态性与嗜睡症表现出更强的关联。该区域包含三个预测基因-NLC 1- A、NLC 1- B和NLC 1- C，暂命名为“发作性睡病候选基因-区域1”，并且NLC 1- A和NLC 1- C在人下丘脑中表达。报告基因分析表明，NLC 1- A启动子区的标记D21 S 0012 m和内含子中的SNP rs 13046884显着影响表达水平。因此，NLC 1- A被认为是一个新的人类嗜睡症的耐药基因。
Human narcolepsy is a hypersomnia that is affected by multiple genetic and environmental factors. One genetic factor strongly associated with narcolepsy is the HLA-DRB1*1501-DQB1*0602 haplotype in the human leukocyte antigen region on chromosome 6, whereas the other genetic factors are not clear. To discover additional candidate regions for susceptibility or resistance to human narcolepsy, we performed a genomewide association study, using 23,244 microsatellite markers. Two rounds of screening with the use of pooled DNAs yielded 96 microsatellite markers (including 16 markers on chromosome 6) with significantly different estimated frequencies in case and control pools. Markers not located on chromosome 6 were evaluated by the individual typing of 95 cases and 95 controls; 30 markers still showed significant associations. A strong association was displayed by a marker on chromosome 21 (21q22.3). The surrounding region was subjected to high-density association mapping with 14 additional microsatellite markers and 74 SNPs. One microsatellite marker (D21S0012m) and two SNPs (rs13048981 and rs13046884) showed strong associations (P < .0005 odds ratios 0.19 - 0.33). These polymorphisms were in a strong linkage disequilibrium, and no other polymorphism in the region showed a stronger association with narcolepsy. The region contains three predicted genes - NLC1- A, NLC1- B, and NLC1- C tentatively named " narcolepsy candidate- region 1 genes," and NLC1- A and NLC1- C were expressed in human hypothalamus. Reporter- gene assays showed that the marker D21S0012m in the promoter region and the SNP rs13046884 in the intron of NLC1- A significantly affected expression levels. Therefore, NLC1- A is considered to be a new resistance gene for human narcolepsy.