title: New susceptibility variants to narcolepsy identified in HLA class II region.
abstract: Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P = 1.4 × 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 × 10(-9), OR = 1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P = 4.1 × 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 × 10(-3), OR = 1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy.
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan miyagawa-taku@umin.ac.jp.
authors.forename: Taku
authors.initials: T
authors.lastname: Miyagawa
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Toyoda
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akane
authors.initials: A
authors.lastname: Hirataka
authors.affiliation: Department of Neuropsychiatry, Akita University, Akita, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanbayashi
authors.affiliation: Department of Neuropsychiatry, Akita University, Akita, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Imanishi
authors.affiliation: Department of Neuropsychiatry, Akita University, Akita, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Sagawa
authors.affiliation: Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan Kotorii Isahaya Hospital, Nagasaki, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Kotorii
authors.affiliation: Kotorii Isahaya Hospital, Nagasaki, Japan.
authors.forename: Tatayu
authors.initials: T
authors.lastname: Kotorii
authors.affiliation: Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hashizume
authors.affiliation: Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan.
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Ogi
authors.affiliation: Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hiejima
authors.affiliation: Sleep Disorder Center, National Center Hospital.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kamei
authors.affiliation: Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hida
authors.affiliation: Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyamoto
authors.affiliation: Department of Psychiatry.
authors.forename: Makoto
authors.initials: M
authors.lastname: Imai
authors.affiliation: Department of Psychiatry and Neurology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yota
authors.initials: Y
authors.lastname: Fujimura
authors.affiliation: Department of Psychiatry and Neurology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Sleep Center, Kuwamizu Hospital, Kumamoto, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Ikegami
authors.affiliation: Department of Psychiatry, Hannan Hospital, Osaka, Japan.
authors.forename: Yamato
authors.initials: Y
authors.lastname: Wada
authors.affiliation: Department of Psychiatry, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
authors.forename: Shunpei
authors.initials: S
authors.lastname: Moriya
authors.affiliation: Department of Neurology, Neuro-Muscular Center, National Omuta Hospital, Fukuoka, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Furuya
authors.affiliation: Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Omata
authors.affiliation: HLA Foundation Laboratory, Kyoto, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Department of HLA Laboratory, Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kashiwase
authors.affiliation: HLA Foundation Laboratory, Kyoto, Japan.
authors.forename: Hiroh
authors.initials: H
authors.lastname: Saji
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Seik-Soon
authors.initials: SS
authors.lastname: Khor
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Maria
authors.initials: M
authors.lastname: Yamasaki
authors.affiliation: Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wada
authors.affiliation: Department of Psychiatry, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ishigooka
authors.affiliation: Department of Psychiatry, Hannan Hospital, Osaka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kuroda
authors.affiliation: Sleep Center, Kuwamizu Hospital, Kumamoto, Japan Department of Stem Cell Biology, Institute of Molecular Genetics and Embryology, Kumamoto University, Kumamoto, Japan Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Aichi, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kume
authors.affiliation: Department of Psychiatry and Neurology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
authors.affiliation: Department of Psychiatry.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Department of Sleep Medicine, Shiga University of Medical Science, Shiga, Japan Japan Foundation for Neuroscience and Mental Health, Tokyo, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Okawa
authors.affiliation: Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirata
authors.affiliation: Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Uchimura
authors.affiliation: Department of Neuropsychiatry, Akita University, Akita, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan Department of Somnology, Tokyo Medical University, Tokyo, Japan and.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Honda
authors.affiliation: Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Mishima
authors.affiliation: Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Honda
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
mesh_terms: D044466:Asian People / Q000235:genetics*; D005802:Genes, MHC Class II; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059868:HLA-DP beta-Chains / Q000235:genetics*; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D006801:Humans; D007564:Japan; D009290:Narcolepsy / Q000235:genetics*
chemical_list: D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen