Abstract
Delayed sleep–wake phase disorder (DSWPD) is a subtype of circadian rhythm sleep–wake disorders, and is characterized by an inability to fall asleep until late at night and wake up at a socially acceptable time in the morning. The study aim was to identify low-frequency nonsense and missense variants that are associated with DSWPD. Candidate variants in circadian rhythm-related genes were extracted by integration of genetic variation databases and in silico assessment. We narrowed down the candidates to six variants. To examine whether the six variants are associated with DSWPD, we performed an association study in 236 Japanese patients with DSWPD and 1436 controls. A low-frequency missense variant (p.Val1205Met) in PER2 showed a significant association with DSWPD (2.5% in cases and 1.1% in controls, P = 0.026, odds ratio (OR) = 2.32). The variant was also associated with idiopathic hypersomnia known to have a tendency toward phase delay (P = 0.038, OR = 2.07). PER2 forms a heterodimer with CRY, and the heterodimer plays an important role in the regulation of circadian rhythms. Val1205 is located in the CRY-binding domain of PER2 and was hypothesized to interact with CRY. The p.Val1205Met substitution could be a potential genetic marker for DSWPD.
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Acknowledgements
The authors are deeply grateful to all participants in this study. This study was supported by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED), Grants-in-Aid for Scientific Research (B) (15H04709) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Grants-in-Aid from the Takeda Science Foundation.
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The laboratory of Dr HK is supported by a donation from Fukuda Lifetech Co., Ltd., Fukuda Life Tech Keiji Co., Ltd., Tanaka Sleep Clinic, Akita Sleep Clinic, and Ai Ai Care Co., Ltd. to the Shiga University of Medical Science. Dr IY has received grants and payment for lectures including service on speakers’ bureaus, and has provided expert testimony for MSD K.K., Takeda Pharmaceutical Co. Ltd., and Eisai Co. Ltd. The other authors have no competing interests to declare.
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Miyagawa, T., Hida, A., Shimada, M. et al. A missense variant in PER2 is associated with delayed sleep–wake phase disorder in a Japanese population. J Hum Genet 64, 1219–1225 (2019). https://doi.org/10.1038/s10038-019-0665-6
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DOI: https://doi.org/10.1038/s10038-019-0665-6
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