Genome-wide analysis of CNV (copy number variation) and their associations with narcolepsy in a Japanese population.
In humans, narcolepsy with cataplexy (narcolepsy) is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Narcolepsy is caused by a reduction in the number of neurons that produce hypocretin (orexin) neuropeptide. Both genetic and environmental factors contribute to the development of narcolepsy.Rare and large copy number variations (CNVs) reportedly play a role in the etiology of a number of neuropsychiatric disorders. Narcolepsy is considered a neurological disorder; therefore, we sought to investigate any possible association between rare and large CNVs and human narcolepsy. We used DNA microarray data and a CNV detection software application, PennCNV-Affy, to detect CNVs in 426 Japanese narcoleptic patients and 562 healthy individuals. Overall, we found a significant enrichment of rare and large CNVs (frequency ≤1%, size ≥100 kb) in the patients (case-control ratio of CNV count=1.54, P=5.00 × 10(-4)). Next, we extended a region-based association analysis by including CNVs with its size ≥30 kb. Rare and large CNVs in PARK2 region showed a significant association with narcolepsy. Four patients were assessed to carry duplications of the gene region, whereas no controls carried the duplication, which was further confirmed by quantitative PCR assay. This duplication was also found in 2 essential hypersomnia (EHS) patients out of 171 patients. Furthermore, a pathway analysis revealed enrichments of gene disruptions by rare and large CNVs in immune response, acetyltransferase activity, cell cycle regulation and regulation of cell development. This study constitutes the first report on the risk association between multiple rare and large CNVs and the pathogenesis of narcolepsy. In the future, replication studies are needed to confirm the associations.
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.
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
Central Research Laboratory, Hitachi, Tokyo, Japan.
Asako
A
Koike
1] Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [2] Department of Clinical Laboratory Medicine, Faculty of Health Science Technology, Bunkyo Gakuin University, Tokyo, Japan.
Aino
A
Nitta
1] Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [2] Department of Clinical Laboratory Medicine, Faculty of Health Science Technology, Bunkyo Gakuin University, Tokyo, Japan.
Kumi
K
Akiyama
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
1] Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan [2] Sleep Control Project, Tokyo Metropolitan Institute of Medical Science, Department of Psychiatry and Behavioral Sciences, Tokyo, Japan.
Makoto
M
Honda
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Katsushi
K
Tokunaga
D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan; D009290:Narcolepsy / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein