학술논문
Epigenome-wide association study of narcolepsy-affected lateral hypothalamic brains, and overlapping DNA methylation profiles between narcolepsy and multiple sclerosis
ORIGINAL ARTICLE
ORIGINAL ARTICLE
Document Type
Report
Author
Source
SLEEP. January 2020, Vol. 43 Issue 1, p1j, 13 p.
Subject
Language
English
ISSN
0161-8105
Abstract
Introduction Narcolepsy with cataplexy (narcolepsy) is a sleep disorder that involves excessive daytime sleepiness and cataplexy; patients generally experience a sudden loss of muscle tone in response to strong emotion. [...]
Narcolepsy with cataplexy is a sleep disorder caused by a deficiency in hypocretin neurons in the lateral hypothalamus (LH). Here we performed an epigenome-wide association study (EWAS) of DNA methylation for narcolepsy and replication analyses using DNA samples extracted from two brain regions: LH (Cases: N = 4; Controls: N = 4) and temporal cortex (Cases: N = 7; Controls: N = 7). Seventy-seven differentially methylated regions (DMRs) were identified in the LH analysis, with the top association of a DMR in the myelin basic protein (MBP) region. Only five DMRs were detected in the temporal cortex analysis. Genes annotated to LH DMRs were significantly associated with pathways related to fatty acid response or metabolism. Two additional analyses applying the EWAS data were performed: (1) investigation of methylation profiles shared between narcolepsy and other disorders and (2) an integrative analysis of DNA methylation data and a genome-wide association study for narcolepsy. The results of the two approaches, which included significant overlap of methylated positions associated with narcolepsy and multiple sclerosis, indicated that the two diseases may partly share their pathogenesis. In conclusion, DNA methylation in LH where loss of orexin-producing neurons occurs may play a role in the pathophysiology of the disease. Statement of Significance In this study, we investigated DNA methylation profile associated with narcolepsy using the lateral hypothalamic (LH) and temporal cortex regions which we stringently cut from the postmortem brain samples. We found that methylation differences between narcolepsy and control samples were detected only in LH and that the most significant differentially methylated region was located in the myelin basic protein region. We also developed novel analyses applying the epigenome-wide association study data and found a significant overlap of DNA methylation profiles between narcolepsy and multiple sclerosis. Neurological deficit associated with myelinogenesis may be a new mechanism involved in the orexin neuronal death. These major findings were confirmed with independent LH-derived control samples. Key words: narcolepsy; DNA methylation; EWAS; lateral hypothalamus.
Narcolepsy with cataplexy is a sleep disorder caused by a deficiency in hypocretin neurons in the lateral hypothalamus (LH). Here we performed an epigenome-wide association study (EWAS) of DNA methylation for narcolepsy and replication analyses using DNA samples extracted from two brain regions: LH (Cases: N = 4; Controls: N = 4) and temporal cortex (Cases: N = 7; Controls: N = 7). Seventy-seven differentially methylated regions (DMRs) were identified in the LH analysis, with the top association of a DMR in the myelin basic protein (MBP) region. Only five DMRs were detected in the temporal cortex analysis. Genes annotated to LH DMRs were significantly associated with pathways related to fatty acid response or metabolism. Two additional analyses applying the EWAS data were performed: (1) investigation of methylation profiles shared between narcolepsy and other disorders and (2) an integrative analysis of DNA methylation data and a genome-wide association study for narcolepsy. The results of the two approaches, which included significant overlap of methylated positions associated with narcolepsy and multiple sclerosis, indicated that the two diseases may partly share their pathogenesis. In conclusion, DNA methylation in LH where loss of orexin-producing neurons occurs may play a role in the pathophysiology of the disease. Statement of Significance In this study, we investigated DNA methylation profile associated with narcolepsy using the lateral hypothalamic (LH) and temporal cortex regions which we stringently cut from the postmortem brain samples. We found that methylation differences between narcolepsy and control samples were detected only in LH and that the most significant differentially methylated region was located in the myelin basic protein region. We also developed novel analyses applying the epigenome-wide association study data and found a significant overlap of DNA methylation profiles between narcolepsy and multiple sclerosis. Neurological deficit associated with myelinogenesis may be a new mechanism involved in the orexin neuronal death. These major findings were confirmed with independent LH-derived control samples. Key words: narcolepsy; DNA methylation; EWAS; lateral hypothalamus.