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

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, Masashi; Tokunaga, Katsushi; Miyagawa, Taku

doi:10.1007/s41105-021-00349-2

Cited by 9 publications

(3 citation statements)

References 43 publications

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“…First, as in all umbrella reviews, our analyses and conclusions are based on previously published reviews (29). Also, we did not set out to report all existing sleepiness assessment tools, and some do not appear in this review, including measures of sleepiness based on functional neuroimaging (92)(93)(94), genetic (95)(96)(97), and biological approaches (98)(99)(100). Furthermore, our selection criteria excluded sleepiness assessment tools developed for pediatric populations and specific diseases (101,102).…”

Section: Limitationsmentioning

confidence: 99%

Sleepiness in adults: An umbrella review of a complex construct

Martin¹,

Lopez²,

Dauvilliers³

et al. 2023

Sleep Medicine Reviews

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Section: Limitationsmentioning

confidence: 99%

Sleepiness in adults: An umbrella review of a complex construct

Martin¹,

Lopez²,

Dauvilliers³

et al. 2023

Sleep Medicine Reviews

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“…A GWAS of KLS found a significant association with variants in TRANK1 region and links between KLS, circadian regulation, and bipolar disorder 11 . Meanwhile, no significant associations between IH and HLA have been observed 12 , and no other genetic variants associated with IH have been clearly identified 13 . Thus, the underlying genetic contribution to IH is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we focused on rare missense and loss-of-function variants in prepro-orexin , OX1R , and OX2R to search for genetic factors of IH because no significant associations with common variants in these gene regions were observed in our GWAS 13 . IH has been reported to be clinically heterogeneous 25 .…”

Section: Introductionmentioning

confidence: 99%

A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia

et al. 2022

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Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10−8, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.

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