TY - JOUR
T1 - Genomewide association analysis of human narcolepsy and a new resistance gene
AU - Kawashima, Minae
AU - Tamiya, Gen
AU - Oka, Akira
AU - Hohjoh, Hirohiko
AU - Juji, Takeo
AU - Ebisawa, Takashi
AU - Honda, Yutaka
AU - Inoko, Hidetoshi
AU - Tokunaga, Katsushi
N1 - Funding Information:
We sincerely thank the patients with narcolepsy who participated in this study. We are indebted to Dr. Jun Ohashi (Department of Human Genetics, Graduate School of Medicine, University of Tokyo), for helpful discussion on statistical analysis, and to Drs. Tomoki Ikuta, Minori Shinya, and Satoshi Makino (Department of Molecular Life Science, Tokai University School of Medicine), for technical help in the genomewide screening. This work was supported by a Grant-in-Aid for Science Research on Priority Areas (Comprehensive Genomics) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology and by a grant from the Kato Memorial Trust for Nambyo Research.
PY - 2006/8
Y1 - 2006/8
N2 - 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.
AB - 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.
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U2 - 10.1086/505539
DO - 10.1086/505539
M3 - Article
C2 - 16826516
AN - SCOPUS:33746472884
SN - 0002-9297
VL - 79
SP - 252
EP - 263
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -