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An approach based on a genome-wide association study reveals candidate loci for narcolepsy

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Abstract

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and a pathological manifestation of rapid eye movement during sleep. Narcoleptic pathogenesis is triggered by both genetic and environmental factors. Recently, development of genome-wide association studies (GWAS) has identified new genetic factors, with many more susceptibility genes yet to be elucidated. Using a new approach that consists of a combination of GWAS and an extensive database search for candidate genes, we picked up 202 candidate genes and performed a replication study in 222 narcoleptic patients and 380 controls. Statistical analysis indicated that six genes, NFATC2, SCP2, CACNA1C, TCRA, POLE, and FAM3D, were associated with narcolepsy (P < 0.001). Some of these associations were further supported by gene expression analyses and an association study in essential hypersomnia (EHS), CNS hypersonia similar to narcolepsy. This novel approach will be applicable to other GWAS in the search of disease-related susceptibility genes.

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Abbreviations

CACNA1C :

Calcium channel voltage-dependent L-type alpha 1C

CHKB :

Choline kinase beta

CI:

Confidence interval

CSF:

Cerebrospinal fluid

CPT1B :

Carnitine palmitoyltransferase 1B

DAD :

Defender against cell death

EHS:

Essential hypersomnia

FAM3D :

Family with sequence similarity 3, member D

GWAS:

Genome-wide association study

HLA:

Human leukocyte antigen

HWE:

Hardy–Weinberg equilibrium

LD:

Linkage disequilibrium

NFATC2 :

Nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 2

NLC1A :

Narcolepsy candidate-region 1 A

OR:

Odds ratio

POLE :

Polymerase (DNA directed), epsilon

REM:

Rapid eye movement

SCP2 :

Sterol carrier protein 2

SNP:

Single nucleotide polymorphism

TCRA :

T cell receptor alpha chain

TNFA :

Tumor necrosis factor alpha

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Acknowledgments

We thank all participants in this study. This study was supported by Grants-in-Aid for Scientific Research on Priority Areas ‘Comprehensive Genomics’ and ‘Applied Genomics’ from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by a Grant-in-Aid for Young Scientists (B), Astellas Foundation for Research on Metabolic Disorders, Takeda Science Foundation, Mitsubishi Pharma Research Foundation and Kowa Life Science Foundation. Ethical approval was obtained from the local institutional review boards of all collaborative organizations. Informed consent was obtained from all subjects.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Mihoko Shimada, Taku Miyagawa, Minae Kawashima & Katsushi Tokunaga

  2. The Sleep Disorders Research Project, Tokyo Institute of Psychiatry, Tokyo, Japan

    Susumu Tanaka & Makoto Honda

  3. Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan

    Yutaka Honda & Makoto Honda

  4. Center for Narcolepsy, Stanford University School of Medicine, Palo Alto, CA, USA

    Minae Kawashima

Authors
  1. Mihoko Shimada
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  2. Taku Miyagawa
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  3. Minae Kawashima
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  4. Susumu Tanaka
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  5. Yutaka Honda
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  6. Makoto Honda
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  7. Katsushi Tokunaga
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Correspondence to Taku Miyagawa.

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Shimada, M., Miyagawa, T., Kawashima, M. et al. An approach based on a genome-wide association study reveals candidate loci for narcolepsy. Hum Genet 128, 433–441 (2010). https://doi.org/10.1007/s00439-010-0862-z

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