Genome-wide association study of idiopathic hypersomnia in a Japanese population

Kotomi Tanida; Mihoko Shimada; Seik-Soon Khor; Hiromi Toyoda; Kayoko Kato; Nozomu Kotorii; Tatayu Kotorii; Yu Ariyoshi; Takao Kato; Hiroshi Hiejima; Motohiro Ozone; Naohisa Uchimura; Azusa Ikegami; Kazuhiko Kume; Takashi Kanbayashi; Aya Imanishi; Yuichi Kamei; Akiko Hida; Yamato Wada; Kenji Kuroda; Masayuki Miyamoto; Koichi Hirata; Masanori Takami; Naoto Yamada; Masako Okawa; Naoto Omata; Hideaki Kondo; Tohru Kodama; Yuichi Inoue; Kazuo Mishima; Makoto Honda; Katsushi Tokunaga; Taku Miyagawa

doi:10.1007/s41105-021-00349-2

Genome-wide association study of idiopathic hypersomnia in a Japanese population

Sleep Biol Rhythms. 2021 Oct 12;20(1):137-148. doi: 10.1007/s41105-021-00349-2. eCollection 2022 Jan.

Authors

Kotomi Tanida¹, Mihoko Shimada^{1

2

3}, Seik-Soon Khor^{1

3}, Hiromi Toyoda¹, Kayoko Kato¹, Nozomu Kotorii^{4

5}, Tatayu Kotorii⁵, Yu Ariyoshi⁶, Takao Kato⁴, Hiroshi Hiejima⁴, Motohiro Ozone⁴, Naohisa Uchimura⁴, Azusa Ikegami⁷, Kazuhiko Kume^{7

8

9}, Takashi Kanbayashi^{10

11}, Aya Imanishi¹², Yuichi Kamei^{13

14}, Akiko Hida¹⁵, Yamato Wada¹⁶, Kenji Kuroda¹⁶, Masayuki Miyamoto¹⁷, Koichi Hirata¹⁷, Masanori Takami¹⁸, Naoto Yamada¹⁸, Masako Okawa^{19

20

21}, Naoto Omata^{22

23}, Hideaki Kondo¹⁰, Tohru Kodama², Yuichi Inoue^{21

24}, Kazuo Mishima^{10

12

15}, Makoto Honda^{2

25}, Katsushi Tokunaga^{1

3}, Taku Miyagawa^{1

2}

Affiliations

¹ Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² 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.
³ Genome Medical Science Project (Toyama), National Center for Global Health and Medicine, Tokyo, Japan.
⁴ Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan.
⁵ Kotorii Isahaya Hospital, Nagasaki, Japan.
⁶ Ariyoshi Sleep Clinic, Fukuoka, Japan.
⁷ Sleep Center, Kuwamizu Hospital, Kumamoto, Japan.
⁸ Department of Stem Cell Biology, Institute of Molecular Genetics and Embryology, Kumamoto University, Kumamoto, Japan.
⁹ Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Aichi, Japan.
¹⁰ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki, Japan.
¹¹ Ibaraki Prefectural Medical Center of Psychiatry, Ibaraki, Japan.
¹² Department of Neuropsychiatry, Akita University Graduate School of Medicine, Akita, Japan.
¹³ Department of Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
¹⁴ Kamisuwa Hospital, Nagano, Japan.
¹⁵ Department of Sleep-Wake Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
¹⁶ Department of Psychiatry, Hannan Hospital, Osaka, Japan.
¹⁷ Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
¹⁸ Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan.
¹⁹ Department of Sleep Medicine, Shiga University of Medical Science, Shiga, Japan.
²⁰ Japan Foundation for Neuroscience and Mental Health, Tokyo, Japan.
²¹ Department of Somnology, Tokyo Medical University, Tokyo, Japan.
²² Department of Nursing, Faculty of Health Science, Fukui Health Science University, Fukui, Japan.
²³ Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
²⁴ Yoyogi Sleep Disorder Center, Neuropsychiatric Research Institute, Tokyo, Japan.
²⁵ Seiwa Hospital, Neuropsychiatric Research Institute, Tokyo, Japan.

Abstract

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 and HLA 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 PDE9A was suggestively associated with IH. rs2250870 was significantly associated with expression levels of PDE9A in not only whole blood but also brain tissues. The leading SNP in the PDE9A region was the same in associations with both IH and PDE9A 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 PDE9A 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.

Supplementary information: The online version contains supplementary material available at 10.1007/s41105-021-00349-2.

Keywords: Genome-wide association study (GWAS); Idiopathic hypersomnia; Phosphodiesterase; Single-nucleotide polymorphisms (SNPs); Sleep.