发作性睡病和原发性睡眠过多的多基因风险评估。
Evaluation of polygenic risks for narcolepsy and essential hypersomnia.
作者信息
Yamasaki Maria, Miyagawa Taku, Toyoda Hiromi, Khor Seik-Soon, Liu Xiaoxi, Kuwabara Hitoshi, Kano Yukiko, Shimada Takafumi, Sugiyama Toshiro, Nishida Hisami, Sugaya Nagisa, Tochigi Mamoru, Otowa Takeshi, Okazaki Yuji, Kaiya Hisanobu, Kawamura Yoshiya, Miyashita Akinori, Kuwano Ryozo, Kasai Kiyoto, Tanii Hisashi, Sasaki Tsukasa, Honda Yutaka, Honda Makoto, Tokunaga Katsushi
机构信息
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
出版信息
J Hum Genet. 2016 Oct;61(10):873-878. doi: 10.1038/jhg.2016.65. Epub 2016 Jun 16.
In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB106:02, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30-50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB106:02, 119 EHS patients without HLA-DQB106:02 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (P=2.30 × 10, P=6.73 × 10) including HLA-DQB106:02 effects and 1.3% (P=2.43 × 10) excluding HLA-DQB106:02 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (P=9.74 × 10). EHS patients with HLA-DQB106:02 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB106:02 even when the effects of HLA-DQB106:02 were excluded (EHS with HLA-DQB106:02: 40.4%, P=7.02 × 10, P=1.34 × 10, EHS without HLA-DQB106:02: 0.4%, P=3.06 × 10). Meanwhile, the polygenic risks for narcolepsy could not explain the onset of panic disorder and autism, suggesting that our results were reasonable.
在人类中，发作性睡病是一种睡眠障碍，其特征为嗜睡、猝倒以及快速眼动（REM）睡眠异常。特发性嗜睡症（EHS）是另一种睡眠障碍，其特征为日间过度嗜睡但无猝倒。人类白细胞抗原（HLA）II类等位基因HLA - DQB106:02是发作性睡病的主要遗传因素。几乎所有发作性睡病患者都是该HLA等位基因的携带者，而在日本，30 - 50%的EHS患者以及12%的健康个体携带此等位基因。发作性睡病和EHS的发病机制被认为有部分共同之处。为评估常见单核苷酸多态性（SNP）对发作性睡病发病的贡献，并评估发作性睡病和EHS的共同遗传背景，我们进行了一项多基因分析，纳入了393例发作性睡病患者、38例携带HLA - DQB106:02的EHS患者、119例不携带HLA - DQB106:02的EHS患者以及1582名健康个体。我们还纳入了376例惊恐障碍患者和213例自闭症患者，以确认结果是否存在偏差。发作性睡病的多基因风险估计可解释58.1%（P = 2.30×10，P = 6.73×10），包括HLA - DQB106:02的影响；排除HLA - DQB106:02的影响后为1.3%（P = 2.43×10）。结果还表明，小效应SNP对发作性睡病的发展有贡献。在日本人群中报道的发作性睡病易感SNP，即肉碱棕榈酰转移酶1B（CPT1B）、T细胞受体α（TRA@）和嘌呤能受体P2Y、G蛋白偶联11（P2RY11），被发现可解释0.8%的发作性睡病发病（P = 9.74×10）。即使排除HLA - DQB106:02的影响，携带HLA - DQB106:02的EHS患者与发作性睡病患者的共同遗传背景估计比不携带HLA - DQB106:02的EHS患者更高（携带HLA - DQB106:02的EHS患者：40.4%，P = 7.02×10，P = 1.34×10；不携带HLA - DQB106:02的EHS患者：0.4%，P = 3.06×10）。同时，发作性睡病的多基因风险无法解释惊恐障碍和自闭症的发病，这表明我们的结果是合理的。
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