Evaluation of polygenic risks for narcolepsy and essential hypersomnia.

ABSTRACT

In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB1*0602, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30-50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB1*0602, 119 EHS patients without HLA-DQB1*0602 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (PHLA-DQB1*0602=2.30 × 10-48, Pwhole genome without HLA-DQB1*0602=6.73 × 10-2) including HLA-DQB1*0602 effects and 1.3% (Pwhole genome without HLA-DQB1*0602=2.43 × 10-2) excluding HLA-DQB1*0602 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (Pwhole genome without HLA-DQB1*0602=9.74 × 10-2). EHS patients with HLA-DQB1*0602 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB1*0602 even when the effects of HLA-DQB1*0602 were excluded (EHS with HLA-DQB1*0602 40.4%, PHLA-DQB1*0602=7.02 × 10-14, Pwhole genome without HLA-DQB1*0602=1.34 × 10-1, EHS without HLA-DQB1*0602 0.4%, Pwhole genome without HLA-DQB1*0602=3.06 × 10-1). Meanwhile, the polygenic risks for narcolepsy could not explain the onset of panic disorder and autism, suggesting that our results were reasonable.