Narcolepsy with
cataplexy, which is a
hypersomnia characterized by
excessive daytime sleepiness and
cataplexy, is a multifactorial disease caused by both genetic and environmental factors. Several genetic factors including
HLA-DQB1*06:02 have been identified; however, the disease etiology is still unclear. Epigenetic modifications, such as DNA methylation, have been suggested to play an important role in the pathogenesis of complex diseases. Here, we examined DNA methylation profiles of blood samples from
narcolepsy and healthy control individuals and performed an epigenome-wide association study (EWAS) to investigate methylation loci associated with
narcolepsy. Moreover, data from the EWAS and a previously performed
narcolepsy genome-wide association study were integrated to search for methylation loci with causal links to the disease. We found that (1) genes annotated to the top-ranked differentially methylated positions (
DMPs) in
narcolepsy were associated with pathways of
hormone secretion and monocarboxylic
acid metabolism. (2) Top-ranked
narcolepsy-associated
DMPs were significantly more abundant in non-CpG island regions and more than 95 per cent of such sites were hypomethylated in
narcolepsy patients. (3) The integrative analysis identified the CCR3 region where both a single methylation site and multiple single-nucleotide polymorphisms were found to be associated with the disease as a candidate region responsible for
narcolepsy. The findings of this study suggest the importance of future replication studies, using methylation technologies with wider genome coverage and/or larger number of samples, to confirm and expand on these results.