Genome-wide association study of idiopathic hypersomnia in a Japanese population
Genome-wide association study of idiopathic hypersomnia in a Japanese population
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日本人群特发性嗜睡症的全基因组关联研究
DOI：
10.1007/s41105-021-00349-2
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发表时间：
2021
影响因子：
1.1
通讯作者：
Miyagawa
中科院分区：
文献类型：
--
作者：
Tanida Kotomi;Shimada Mihoko;Khor Seik-Soon;Toyoda Hiromi;Kato Kayoko;Kotorii Nozomu;Kotorii Tatayu;Ariyoshi Yu;Kato Takao;Hiejima Hiroshi;Ozone Motohiro;Uchimura Naohisa;他15名;Kodama Tohru;Inoue Yuichi;Mishima Kazuo;Honda Makoto;Tokunaga Katsushi;Miyagawa
特发性嗜睡症（IH）是一种罕见的睡眠障碍，其特征是白天过度嗜睡，醒来时非常困难，睡眠时间延长。与公认的嗜睡症1型相反，IH的病因学仍然知之甚少。虽然在IH患者中观察到家族聚集性，但尚未发现IH的易感基因座。1型发作性睡病与人类白细胞抗原（HLA）-DQB 1 *06：02密切相关;然而，IH和HLA等位基因之间没有显著相关性的报道。为了确定影响IH易感性的遗传变异，我们进行了一项全基因组关联研究（GWAS）和两项重复研究，共涉及414名日本IH患者和6587名健康日本人。对这三项研究的荟萃分析发现，没有单核苷酸多态性（SNP）达到全基因组显著性水平。然而，我们确定了IH的几个候选SNP。例如，PDE 9A内含子内的一个常见遗传变异（rs 2250870）与IH相关。rs 2250870不仅与全血中PDE 9A的表达水平显著相关，而且与脑组织中PDE 9A的表达水平显著相关。PDE 9A区域的前导SNP与IH和PDE 9A表达的相关性相同。PDE 9A是治疗多种脑部疾病的潜在靶点，如抑郁症、精神分裂症和阿尔茨海默病。由于观察到rs 2250870风险等位基因的PDE 9A表达水平更高，因此有必要检查已证实对神经生理学和认知功能有影响的PDE 9A抑制剂是否有助于开发IH的新治疗方法。本研究构成了与IH相关的遗传变异的第一个GWAS。将需要更大规模的重复研究来确认这些关联。
Idiopathic hypersomnia (IH) is a rare sleep disorder characterized by excessive daytime sleepiness, great difficulty upon awakening, and prolonged sleep time. In contrast to narcolepsy type 1, which is a well-recognized hypersomnia, the etiology of IH remains poorly understood. No susceptibility loci for IH have been identified, although familial aggregations have been observed among patients with IH. Narcolepsy type 1 is strongly associated with human leukocyte antigen(HLA)-DQB1*06:02; however, no significant associations between IH andHLAalleles have been reported. To identify genetic variants that affect susceptibility to IH, we performed a genome-wide association study (GWAS) and two replication studies involving a total of 414 Japanese patients with IH and 6587 healthy Japanese individuals. A meta-analysis of the three studies found no single-nucleotide polymorphisms (SNPs) that reached the genome-wide significance level. However, we identified several candidate SNPs for IH. For instance, a common genetic variant (rs2250870) within an intron ofPDE9Awas suggestively associated with IH. rs2250870 was significantly associated with expression levels ofPDE9Ain not only whole blood but also brain tissues. The leading SNP in thePDE9Aregion was the same in associations with both IH andPDE9Aexpression. PDE9A is a potential target in the treatment of several brain diseases, such as depression, schizophrenia, and Alzheimer’s disease. It will be necessary to examine whether PDE9A inhibitors that have demonstrated effects on neurophysiologic and cognitive function can contribute to the development of new treatments for IH, as higher expression levels ofPDE9Awere observed with regard to the risk allele of rs2250870. The present study constitutes the first GWAS of genetic variants associated with IH. A larger replication study will be required to confirm these associations.