Evaluation of polygenic risks for narcolepsy and essential hypersomnia.
In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB1*06:02, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30-50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB1*06:02, 119 EHS patients without HLA-DQB1*06:02 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (PHLA-DQB1*06:02=2.30 × 10-48, Pwhole genome without HLA-DQB1*06:02=6.73 × 10-2) including HLA-DQB1*06:02 effects and 1.3% (Pwhole genome without HLA-DQB1*06:02=2.43 × 10-2) excluding HLA-DQB1*06:02 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (Pwhole genome without HLA-DQB1*06:02=9.74 × 10-2). EHS patients with HLA-DQB1*06:02 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB1*06:02 even when the effects of HLA-DQB1*06:02 were excluded (EHS with HLA-DQB1*06:02: 40.4%, PHLA-DQB1*06:02=7.02 × 10-14, Pwhole genome without HLA-DQB1*06:02=1.34 × 10-1, EHS without HLA-DQB1*06:02: 0.4%, Pwhole genome without HLA-DQB1*06:02=3.06 × 10-1). Meanwhile, the polygenic risks for narcolepsy could not explain the onset of panic disorder and autism, suggesting that our results were reasonable.
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Maria
M
Yamasaki
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Taku
T
Miyagawa
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Hiromi
H
Toyoda
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Seik-Soon
SS
Khor
Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, Kanagawa, Japan.
Xiaoxi
X
Liu
Department of Child Psychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Hitoshi
H
Kuwabara
Department of Child Psychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Yukiko
Y
Kano
Division for Counseling and Support, The University of Tokyo, Tokyo, Japan.
Takafumi
T
Shimada
Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, Shizuoka, Japan.
Toshiro
T
Sugiyama
Asunaro Hospital for Child and Adolescent Psychiatry, Mie, Japan.
Hisami
H
Nishida
Department of Epidemiology and Public Health, Yokohama City University Graduate school of Medicine, Kanagawa, Japan.
Nagisa
N
Sugaya
Teikyo University Hospital, Tokyo, Japan.
Mamoru
M
Tochigi
Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Takeshi
T
Otowa
Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan.
Yuji
Y
Okazaki
Panic Disorder Research Center, Warakukai Med Corp, Tokyo, Japan.
Hisanobu
H
Kaiya
Department of Psychiatry, Shonan Kamakura General Hospital, Kanagawa, Japan.
Yoshiya
Y
Kawamura
Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
Akinori
A
Miyashita
Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
Ryozo
R
Kuwano
Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Kiyoto
K
Kasai
Department of Psychiatry, Graduate School of Medicine, Mie University, Mie, Japan.
Hisashi
H
Tanii
Department of Physical and Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan.
Tsukasa
T
Sasaki
Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan.
Yutaka
Y
Honda
Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.|Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan.
Makoto
M
Honda
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Katsushi
K
Tokunaga
D000483:Alleles; D055028:Comparative Genomic Hybridization; D006970:Disorders of Excessive Somnolence / Q000175:diagnosis / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059866:HLA-DQ beta-Chains / Q000235:genetics; D006801:Humans; D020412:Multifactorial Inheritance; D009290:Narcolepsy / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012306:Risk
D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen