Genome-wide association study of HLA-DQB1*06:02 negative essential hypersomnia

PeerJ. 2013 Apr 16:1:e66. doi: 10.7717/peerj.66. Print 2013.


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.

Keywords: CRAT; EHS; Essential hypersomnia; HLA-DQB1*06:02; NAP5; NCKAP5; Narcolepsy; Narcolepsy with cataplexy; SPRED1.

Grants and funding

This study was supported by Grants-in-Aid for Young Scientists (A) (23689022) and Scientific Research on Innovative Areas (22133008) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Grants-in-Aid from “Takeda Science Foundation” and “SENSHIN Medical Research Foundation”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.