Evaluation of polygenic risks for narcolepsy and essential hypersomnia

Maria Yamasaki; Taku Miyagawa; Hiromi Toyoda; Seik-Soon Khor; Xiaoxi Liu; Hitoshi Kuwabara; Yukiko Kano; Takafumi Shimada; Toshiro Sugiyama; Hisami Nishida; Nagisa Sugaya; Mamoru Tochigi; Takeshi Otowa; Yuji Okazaki; Hisanobu Kaiya; Yoshiya Kawamura; Akinori Miyashita; Ryozo Kuwano; Kiyoto Kasai; Hisashi Tanii; Tsukasa Sasaki; Yutaka Honda; Makoto Honda; Katsushi Tokunaga

doi:10.1038/jhg.2016.65

Evaluation of polygenic risks for narcolepsy and essential hypersomnia

J Hum Genet. 2016 Oct;61(10):873-878. doi: 10.1038/jhg.2016.65. Epub 2016 Jun 16.

Authors

Maria Yamasaki¹, Taku Miyagawa^{1

2}, Hiromi Toyoda¹, Seik-Soon Khor¹, Xiaoxi Liu³, Hitoshi Kuwabara⁴, Yukiko Kano⁴, Takafumi Shimada⁵, Toshiro Sugiyama⁶, Hisami Nishida⁷, Nagisa Sugaya⁸, Mamoru Tochigi⁹, Takeshi Otowa¹⁰, Yuji Okazaki¹¹, Hisanobu Kaiya¹², Yoshiya Kawamura¹³, Akinori Miyashita¹⁴, Ryozo Kuwano¹⁴, Kiyoto Kasai¹⁰, Hisashi Tanii¹⁵, Tsukasa Sasaki¹⁶, Yutaka Honda¹⁷, Makoto Honda^{2

17}, Katsushi Tokunaga¹

Affiliations

¹ Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
³ Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, Kanagawa, Japan.
⁴ Department of Child Psychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁵ Division for Counseling and Support, The University of Tokyo, Tokyo, Japan.
⁶ Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, Shizuoka, Japan.
⁷ Asunaro Hospital for Child and Adolescent Psychiatry, Mie, Japan.
⁸ Department of Epidemiology and Public Health, Yokohama City University Graduate school of Medicine, Kanagawa, Japan.
⁹ Teikyo University Hospital, Tokyo, Japan.
¹⁰ Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹¹ Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan.
¹² Panic Disorder Research Center, Warakukai Med Corp, Tokyo, Japan.
¹³ Department of Psychiatry, Shonan Kamakura General Hospital, Kanagawa, Japan.
¹⁴ Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
¹⁵ Department of Psychiatry, Graduate School of Medicine, Mie University, Mie, Japan.
¹⁶ Department of Physical and Health Education, Graduate School of Education, The University of Tokyo, Tokyo, Japan.
¹⁷ Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan.

PMID: 27305985
DOI: 10.1038/jhg.2016.65

Abstract

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% (P_{HLA-DQB1*06:02}=2.30 × 10^-48, P_{whole genome without HLA-DQB1*06:02}=6.73 × 10^-2) including HLA-DQB1*06:02 effects and 1.3% (P_{whole 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 (P_{whole 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%, P_{HLA-DQB1*06:02}=7.02 × 10^-¹⁴, P_{whole genome without HLA-DQB1*06:02}=1.34 × 10^-¹, EHS without HLA-DQB1*06:02: 0.4%, P_{whole 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.

MeSH terms

Alleles
Comparative Genomic Hybridization
Disorders of Excessive Somnolence / diagnosis
Disorders of Excessive Somnolence / genetics*
Genetic Association Studies*
Genetic Predisposition to Disease*
Genotype
HLA-DQ beta-Chains / genetics
Humans
Multifactorial Inheritance*
Narcolepsy / diagnosis
Narcolepsy / genetics*
Phenotype
Polymorphism, Single Nucleotide
Risk

Substances

HLA-DQ beta-Chains
HLA-DQB1 antigen