approach based on a genome-wide association study reveals candidate loci for narcolepsy

• Published in: Human genetics 2010-10, Vol.128 (4), p.433-441
• Main Authors: Shimada, Mihoko, Miyagawa, Taku, Kawashima, Minae, Tanaka, Susumu, Honda, Yutaka, Honda, Makoto, Tokunaga, Katsushi
• Format: Article
• Language: English
• Subjects: Analysis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Calcium Channels, L-Type - genetics; Carrier Proteins - genetics; Chi-Square Distribution; Classical genetics, quantitative genetics, hybrids; Cytokines - genetics; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; DNA Polymerase II - genetics; Eye movements; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; Gene Frequency; Gene Function; Genes; Genetic Predisposition to Disease - genetics; Genetic testing; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study - methods; Genomes; Genomics; Genotype; Haplotypes; HLA-DQ Antigens - genetics; HLA-DQ beta-Chains; HLA-DR Antigens - genetics; HLA-DRB1 Chains; Human; Human Genetics; Humans; Kinases; Leukocytes; Linkage Disequilibrium; Medical sciences; Membrane Glycoproteins - genetics; Metabolic Diseases; Molecular Medicine; Narcolepsy; Narcolepsy - genetics; Narcolepsy - pathology; Nervous system (semeiology, syndromes); Neurology; NFATC Transcription Factors - genetics; Original Investigation; Pathogenesis; Poly-ADP-Ribose Binding Proteins; Polymorphism, Single Nucleotide; Receptors, Antigen, T-Cell, alpha-beta - genetics; Reverse Transcriptase Polymerase Chain Reaction; Sleep; Sleep disorders; T cell receptors
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-010-0862-z

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.