Human Genetics

, Volume 128, Issue 4, pp 433–441

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

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

DOI: 10.1007/s00439-010-0862-z

Cite this article as:
Shimada, M., Miyagawa, T., Kawashima, M. et al. Hum Genet (2010) 128: 433. doi:10.1007/s00439-010-0862-z

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.

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

Supplementary material

439_2010_862_MOESM1_ESM.ppt (311 kb)
Supplementary material 1 (PPT 311 kb)
439_2010_862_MOESM2_ESM.ppt (46 kb)
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)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Mihoko Shimada
    • 1
  • Taku Miyagawa
    • 1
  • 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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