Genomewide association analysis of human narcolepsy and a new resistance gene

Minae Kawashima, Gen Tamiya, Akira Oka, Hirohiko Hohjoh, Takeo Juji, Takashi Ebisawa, Yutaka Honda, Hidetoshi Inoko, Katsushi Tokunaga

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)


Human narcolepsy is a hypersomnia that is affected by multiple genetic and environmental factors. One genetic factor strongly associated with narcolepsy is the HLA-DRB1*1501-DQB1*0602 haplotype in the human leukocyte antigen region on chromosome 6, whereas the other genetic factors are not clear. To discover additional candidate regions for susceptibility or resistance to human narcolepsy, we performed a genomewide association study, using 23,244 microsatellite markers. Two rounds of screening with the use of pooled DNAs yielded 96 microsatellite markers (including 16 markers on chromosome 6) with significantly different estimated frequencies in case and control pools. Markers not located on chromosome 6 were evaluated by the individual typing of 95 cases and 95 controls; 30 markers still showed significant associations. A strong association was displayed by a marker on chromosome 21 (21q22.3). The surrounding region was subjected to high-density association mapping with 14 additional microsatellite markers and 74 SNPs. One microsatellite marker (D21S0012m) and two SNPs (rs13048981 and rs13046884) showed strong associations (P < .0005; odds ratios 0.19-0.33). These polymorphisms were in a strong linkage disequilibrium, and no other polymorphism in the region showed a stronger association with narcolepsy. The region contains three predicted genes-NLC1-A, NLC1-B, and NLC1-C-tentatively named "narcolepsy candidate-region 1 genes," and NLC1-A and NLC1-C were expressed in human hypo1halamus. Reporter-gene assays showed that the marker D21S0012m in the promoter region and the SNP rs13046884 in the intron of NLCl-A significantly affected expression levels. Therefore, NLC1-A is considered to be a new resistance gene for human narcolepsy.

Original languageEnglish
Pages (from-to)252-263
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - 2006 Aug


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