An approach based on a genome-wide association study reveals candidate loci for narcolepsy.
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.
Shimada
Mihoko
M
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Miyagawa
Taku
T
Kawashima
Minae
M
Tanaka
Susumu
S
Honda
Yutaka
Y
Honda
Makoto
M
Tokunaga
Katsushi
K
D020746:Calcium Channels, L-Type / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D016009:Chi-Square Distribution; D016207:Cytokines / Q000235:genetics; D004257:DNA Polymerase II / Q000235:genetics; D020869:Gene Expression Profiling; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D015810:Linkage Disequilibrium; D008562:Membrane Glycoproteins / Q000235:genetics; D050778:NFATC Transcription Factors / Q000235:genetics; D009290:Narcolepsy / Q000235:genetics* / Q000473:pathology; D000075223:Poly-ADP-Ribose Binding Proteins; D020641:Polymorphism, Single Nucleotide; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D002352:Carrier Proteins; D016207:Cytokines; C553191:FAM3D protein, human; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C072087:sterol carrier proteins; D004257:DNA Polymerase II; C119525:POLE protein, human