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, Ikegami Azusa, Kume Kazuhiko, Kanbayashi Takashi, Imanishi Aya, Kamei Yuichi, Hida Akiko, Wada Yamato, Kuroda Kenji, Miyamoto Masayuki, Hirata Koichi, Takami Masanori, Yamada Naoto, Okawa Masako, Omata Naoto, Kondo Hideaki, Kodama Tohru, Inoue Yuichi, Mishima Kazuo, Honda Makoto, Tokunaga Katsushi, Miyagawa Taku
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, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506 Japan.
Sleep Biol Rhythms. 2021 Oct 12;20(1):137-148. doi: 10.1007/s41105-021-00349-2. eCollection 2022 Jan.
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 ; however, no significant associations between IH and alleles 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 of was suggestively associated with IH. rs2250870 was significantly associated with expression levels of in not only whole blood but also brain tissues. The leading SNP in the region was the same in associations with both IH and expression. 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 of were 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.
The online version contains supplementary material available at 10.1007/s41105-021-00349-2.
特发性嗜睡症（IH）是一种罕见的睡眠障碍，其特征为日间过度嗜睡、觉醒困难以及睡眠时间延长。与1型发作性睡病这种已得到充分认识的嗜睡症不同，IH的病因仍知之甚少。尽管在IH患者中观察到家族聚集现象，但尚未确定IH的易感基因座。1型发作性睡病与人类白细胞抗原密切相关；然而，尚未报道IH与等位基因之间存在显著关联。为了确定影响IH易感性的基因变异，我们进行了一项全基因组关联研究（GWAS）以及两项复制研究，共纳入414例日本IH患者和6587名健康日本个体。对这三项研究的荟萃分析未发现达到全基因组显著性水平的单核苷酸多态性（SNP）。然而，我们确定了几个IH的候选SNP。例如，位于某个基因内含子内的一个常见基因变异（rs2250870）与IH存在提示性关联。rs2250870不仅与全血中的该基因表达水平显著相关，还与脑组织中的表达水平显著相关。该基因区域中的主要SNP在与IH及该基因表达的关联中是相同的。磷酸二酯酶9A（PDE9A）是治疗多种脑部疾病（如抑郁症、精神分裂症和阿尔茨海默病）的潜在靶点。鉴于在rs2250870的风险等位基因方面观察到该基因表达水平较高，有必要研究已证明对神经生理和认知功能有影响的PDE9A抑制剂是否有助于开发针对IH的新疗法。本研究是首次针对与IH相关的基因变异进行的GWAS。需要更大规模的复制研究来证实这些关联。
在线版本包含可在10.1007/s41105-021-00349-2获取的补充材料。
