Human Genetics

, Volume 128, Issue 4, pp 433–441 | Cite as

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

  • Mihoko Shimada
  • Taku MiyagawaEmail author
  • Minae Kawashima
  • Susumu Tanaka
  • Yutaka Honda
  • Makoto Honda
  • Katsushi Tokunaga
Original Investigation


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.


Human Leukocyte Antigen Excessive Daytime Sleepiness Narcolepsy UCSC Genome Browser Relative Gene Expression Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Calcium channel voltage-dependent L-type alpha 1C


Choline kinase beta


Confidence interval


Cerebrospinal fluid


Carnitine palmitoyltransferase 1B


Defender against cell death


Essential hypersomnia


Family with sequence similarity 3, member D


Genome-wide association study


Human leukocyte antigen


Hardy–Weinberg equilibrium


Linkage disequilibrium


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


Narcolepsy candidate-region 1 A


Odds ratio


Polymerase (DNA directed), epsilon


Rapid eye movement


Sterol carrier protein 2


Single nucleotide polymorphism


T cell receptor alpha chain


Tumor necrosis factor alpha



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.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

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Supplementary material 1 (PPT 311 kb)
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Supplementary material 2 (PPT 46 kb)
439_2010_862_MOESM3_ESM.doc (34 kb)
Supplementary material 3 (DOC 33 kb)
439_2010_862_MOESM4_ESM.xls (280 kb)
Supplementary material 4 (XLS 280 kb)


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Mihoko Shimada
    • 1
  • Taku Miyagawa
    • 1
    Email author
  • Minae Kawashima
    • 1
    • 4
  • Susumu Tanaka
    • 2
  • Yutaka Honda
    • 3
  • Makoto Honda
    • 2
    • 3
  • Katsushi Tokunaga
    • 1
  1. 1.Department of Human Genetics, Graduate School of MedicineThe University of TokyoTokyoJapan
  2. 2.The Sleep Disorders Research ProjectTokyo Institute of PsychiatryTokyoJapan
  3. 3.Japan Somnology CenterNeuropsychiatric Research InstituteTokyoJapan
  4. 4.Center for NarcolepsyStanford University School of MedicinePalo AltoUSA

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