Essential
hypersomnia (EHS), a
sleep disorder characterized by
excessive daytime sleepiness, can be divided into two broad classes based on the presence or absence of the
HLA-DQB1*06:02 allele.
HLA-DQB1*06:02-positive EHS and
narcolepsy with
cataplexy are associated with the same susceptibility genes. In contrast, there are fewer studies of
HLA-DQB1*06:02 negative EHS which, we hypothesized, involves a different pathophysiological pathway than does
narcolepsy with
cataplexy. In order to identify susceptibility genes associated with
HLA-DQB1*06:02 negative EHS, we conducted a genome-wide association study (GWAS) of 125 unrelated Japanese EHS patients lacking the
HLA-DQB1*06:02 allele and 562 Japanese healthy controls. A comparative study was also performed on 268
HLA-DQB1*06:02 negative Caucasian
hypersomnia patients and 1761
HLA-DQB1*06:02 negative Caucasian healthy controls. We identified three SNPs that each represented a unique locus- rs16826005 (P = 1.02E-07; NCKAP5), rs11854769 (P = 6.69E-07; SPRED1), and rs10988217 (P = 3.43E-06; CRAT) that were associated with an increased risk of EHS in this Japanese population. Interestingly, rs10988217 showed a similar tendency in its association with both
HLA-DQB1*06:02 negative EHS and
narcolepsy with
cataplexy in both Japanese and Caucasian populations. This is the first GWAS of
HLA-DQB1*06:02 negative EHS, and the identification of these three new susceptibility loci should provide additional insights to the pathophysiological pathway of this condition.