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PMID: 16826516 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Genomewide association analysis of human narcolepsy and a new resistance gene.

American journal of human genetics ·Vol. 79 ·No. 2 ·2006-08-00 ·Pages 252-63

Kawashima M, Tamiya G, Oka A, Hohjoh H, Juji T, Ebisawa T, Honda Y, Inoko H, Tokunaga K

Abstract

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 hypothalamus. Reporter-gene assays showed that the marker D21S0012m in the promoter region and the SNP rs13046884 in the intron of NLC1-A significantly affected expression levels. Therefore, NLC1-A is considered to be a new resistance gene for human narcolepsy.

MeSH Terms
Genetic Markers/genetics Genetic Predisposition to Disease Genome, Human HLA Antigens/genetics Humans Microsatellite Repeats Molecular Sequence Data Narcolepsy/genetics
Chemicals
Genetic Markers HLA Antigens
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Kawashima Minae
Department of Sleep Disorder Research (Alfresa), Graduate School of Medicine, University of Tokyo, Japan.
Tamiya Gen
Oka Akira
Hohjoh Hirohiko
Juji Takeo
Ebisawa Takashi
Honda Yutaka
Inoko Hidetoshi
Tokunaga Katsushi
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/505539
Published
2006-08-00
Epub
2006-00-13
Pages
252-63
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1559501
Subset
IM
External Links
PubMed source DOI: 10.1086/505539 PMC Full Text View journal details
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