EIF3G is associated with narcolepsy across ethnicities
EIF3G is associated with narcolepsy across ethnicities
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DOI：
10.1038/ejhg.2015.4
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发表时间：
2015-10-01
影响因子：
5.2
通讯作者：
Kornum, Birgitte R.
中科院分区：
文献类型：
--
作者：
Holm, Anja;Lin, Ling;Kornum, Birgitte R.
1型发作性睡病，一种影响下丘脑泌素（食欲素）神经元的自身免疫性疾病，与HLA-DQB 1（星星）密切相关。在与该疾病相关的多态性中，单核苷酸多态性rs 2305795（c。（星星）638 G>A）位于P2 RY 11基因内。P2 RY 11位于哺乳动物和斑马鱼中保守的同线性区域，包含PPAN、EIF 3G和DNMT 1（DNA甲基转移酶1）。由于DNMT 1突变导致一种罕见的显性发作性睡病，与耳聋、小脑性共济失调和痴呆相关，我们质疑在散发性发作性睡病中与P2 RY 11的关联是否继发于与DNMT 1的连锁不平衡。基于来自欧洲和中国血统的两个队列的全基因组关联数据，我们发现P2 RY 11/EIF 3G和DNMT 1之间的嗜睡症关联信号急剧下降，这表明与嗜睡症的关联没有延伸到DNMT 1基因区域。有趣的是，通过跨种族定位，我们在EIF 3G基因中发现了一个新的单核苷酸多态性rs3826784（c.596- 260 A>G），该多态性也与发作性睡病相关。疾病相关等位基因增加EIF 3G mRNA表达。EIF 3G位于发作性睡病的风险位点，并且EIF 3G表达与PPAN和P2 RY 11表达相关。这表明可能受多态性影响的共同调节机制与嗜睡症相关。
Type 1 narcolepsy, an autoimmune disease affecting hypocretin (orexin) neurons, is strongly associated with HLA-DQB1(star)06:02. Among polymorphisms associated with the disease is single-nucleotide polymorphism rs2305795 (c.(star)638G>A) located within the P2RY11 gene. P2RY11 is in a region of synteny conserved in mammals and zebrafish containing PPAN, EIF3G and DNMT1 (DNA methyltransferase 1). As mutations in DNMT1 cause a rare dominant form of narcolepsy in association with deafness, cerebellar ataxia and dementia, we questioned whether the association with P2RY11 in sporadic narcolepsy could be secondary to linkage disequilibrium with DNMT1. Based on genome-wide association data from two cohorts of European and Chinese ancestry, we found that the narcolepsy association signal drops sharply between P2RY11/EIF3G and DNMT1, suggesting that the association with narcolepsy does not extend into the DNMT1 gene region. Interestingly, using transethnic mapping, we identified a novel single-nucleotide polymorphism rs3826784 (c.596-260A>G) in the EIF3G gene also associated with narcolepsy. The disease-associated allele increases EIF3G mRNA expression. EIF3G is located in the narcolepsy risk locus and EIF3G expression correlates with PPAN and P2RY11 expression. This suggests shared regulatory mechanisms that might be affected by the polymorphism and are of relevance to narcolepsy.