Letter abstract
Nature Genetics 40, 1324 - 1328 (2008)
Published online: 28 September 2008 | doi:10.1038/ng.231
Variant between CPT1B and CHKB associated with susceptibility to narcolepsy
Taku Miyagawa1, Minae Kawashima1,2, Nao Nishida1, Jun Ohashi1, Ryosuke Kimura1,3, Akihiro Fujimoto1, Mihoko Shimada1, Shinichi Morishita4, Takashi Shigeta4, Ling Lin5, Seung-Chul Hong6, Juliette Faraco5, Yoon-Kyung Shin6, Jong-Hyun Jeong6, Yuji Okazaki7, Shoji Tsuji8,9, Makoto Honda10,11, Yutaka Honda11, Emmanuel Mignot5,12 & Katsushi Tokunaga1
Narcolepsy (hypocretin deficiency), a sleep disorder characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities, is tightly associated with HLA-DRB1*1501 (M17378) and HLA-DQB1*0602 (M20432). Susceptibility genes other than those in the HLA region are also likely involved. We conducted a genome-wide association study using 500K SNP microarrays in 222 Japanese individuals with narcolepsy and 389 Japanese controls, with replication of top hits in 159 Japanese individuals with narcolepsy and 190 Japanese controls, followed by the testing of 424 Koreans, 785 individuals of European descent and 184 African Americans. rs5770917, a SNP located between CPT1B and CHKB, was associated with narcolepsy in Japanese (rs5770917[C], odds ratio (OR) = 1.79, combined P = 4.4 
10-7) and other ancestry groups (OR = 1.40, P = 0.02). Real-time quantitative PCR assays in white blood cells indicated decreased CPT1B and CHKB expression in subjects with the C allele, suggesting that a genetic variant regulating CPT1B or CHKB expression is associated with narcolepsy. Either of these genes is a plausible candidate, as CPT1B regulates 
-oxidation, a pathway involved in regulating theta frequency during REM sleep, and CHKB is an enzyme involved in the metabolism of choline, a precursor of the REM- and wake-regulating neurotransmitter acetylcholine.
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
- Department of Sleep Disorder Research, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
- Department of Forensic Medicine, Tokai University School of Medicine, Ishehara 259-1100, Japan.
- Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-0000, Japan.
- Center for Narcolepsy, Stanford University School of Medicine, Palo Alto, California 94305, USA.
- Department of Neuropsychiatry, St. Vincent's Hospital, The Catholic University of Korea, Suwon 442-723, Republic of Korea.
- Tokyo Metropolitan Matsuzawa Hospital, Tokyo 156-0057, Japan.
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
- The 21st Century COE Program, Center for Integrated Brain Medical Science, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
- Department of Sleep Disorders Research, Tokyo Institute of Psychiatry, Tokyo 156-8585, Japan.
- Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo 151-0053, Japan.
- Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, California 94305, USA.
Correspondence to: Katsushi Tokunaga1 e-mail: tokunaga@m.u-tokyo.ac.jp
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