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Hum Mol Genet. 2015 Feb 1;24(3):891-8. doi: 10.1093/hmg/ddu480. Epub 2014 Sep 25.

New susceptibility variants to narcolepsy identified in HLA class II region.

Author information

1
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan miyagawa-taku@umin.ac.jp.
2
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
3
Department of Neuropsychiatry, Akita University, Akita, Japan.
4
Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan Kotorii Isahaya Hospital, Nagasaki, Japan.
5
Kotorii Isahaya Hospital, Nagasaki, Japan.
6
Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan.
7
Sleep Disorder Center, National Center Hospital.
8
Department of Psychophysiology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
9
Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
10
Department of Psychiatry.
11
Department of Psychiatry and Neurology, Asahikawa Medical University, Asahikawa, Japan.
12
Sleep Center, Kuwamizu Hospital, Kumamoto, Japan.
13
Department of Psychiatry, Hannan Hospital, Osaka, Japan.
14
Department of Psychiatry, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
15
Department of Neurology, Neuro-Muscular Center, National Omuta Hospital, Fukuoka, Japan.
16
Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan.
17
Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
18
HLA Foundation Laboratory, Kyoto, Japan.
19
Department of HLA Laboratory, Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.
20
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.
21
Department of Sleep Medicine, Shiga University of Medical Science, Shiga, Japan Japan Foundation for Neuroscience and Mental Health, Tokyo, Japan.
22
Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan Department of Somnology, Tokyo Medical University, Tokyo, Japan and.
23
Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan.
24
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.

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.

PMID:
25256355
DOI:
10.1093/hmg/ddu480
[Indexed for MEDLINE]

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