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Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen  HLA-DQB1*06:02. DQB1*06:02  is common in the general population (10–30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study,  HLA-DQB1  in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether  HLA-DQB1  alleles located in trans of  DQB1*06:02  are associated with narcolepsy. The strongest association was with  DQB1*06:01  ( P  = 1.4 × 10 −10 , odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of  DQB1*03:02  were also found ( P  = 2.5 × 10 −9 , OR = 1.97). A comparison between  DQB1*06:02  heterozygous cases and controls revealed dominant protective effects of  DQB1*06:01  and  DQB1*05:01 . In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of  HLA-DQB1  was performed to determine whether there were other independent  HLA  associations outside of  HLA-DQB1 . This analysis revealed associations at  HLA-DPB1  in the  HLA  class II region (rs3117242,  P  = 4.1 × 10 −5 , OR = 2.45;  DPB1*05:01 ,  P  = 8.1 × 10 −3 , OR = 1.39). These results indicate that complex  HLA  class II associations contribute to the genetic predisposition to narcolepsy.

New susceptibility variants to narcolepsy identified in HLA class II region