Variant between CPT1B and CHKB associated with susceptibility to narcolepsy

• Published in: Nature genetics Vol. 40; no. 11; pp. 1324 - 1328
• Main Authors: Miyagawa, Taku, Kawashima, Minae, Nishida, Nao, Ohashi, Jun, Kimura, Ryosuke, Fujimoto, Akihiro, Shimada, Mihoko, Morishita, Shinichi, Shigeta, Takashi, Lin, Ling, Hong, Seung-Chul, Faraco, Juliette, Shin, Yoon-Kyung, Jeong, Jong-Hyun, Okazaki, Yuji, Tsuji, Shoji, Honda, Makoto, Honda, Yutaka, Mignot, Emmanuel, Tokunaga, Katsushi
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2008; Nature Publishing Group
• Subjects: African Americans; Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carnitine O-Palmitoyltransferase - genetics; Case-Control Studies; Choline Kinase - genetics; Circadian rhythm; Disease susceptibility; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic; Gene Function; Genetic aspects; Genetic Predisposition to Disease; Genetic variance; Genetic variation; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human - genetics; Genomics; Human Genetics; Humans; letter; Linkage Disequilibrium - genetics; Medical sciences; Mutation - genetics; Narcolepsy; Narcolepsy - enzymology; Narcolepsy - genetics; Nervous system (semeiology, syndromes); Neurology; Risk factors; Sleep disorders; Japan; Variant; Sleep disorder; Nervous system diseases; Narcolepsy; Neurological disorder
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.231

Katsushi Tokunaga and colleagues report the results of a genome-wide association study for narcolepsy. A variant on chromosome 22 between CPT1B and CHKB is associated with increased risk of the disorder. Both gene products have previously been linked to the physiology of sleep, making each a potential susceptibility factor. 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 β-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.