title: Genetic and metabolic characterization of insomnia.
abstract: Insomnia is reported to chronically affect 10∼15% of the adult population. However, very little is known about the genetics and metabolism of insomnia. Here we surveyed 10,038 Korean subjects whose genotypes have been previously profiled on a genome-wide scale. About 16.5% reported insomnia and displayed distinct metabolic changes reflecting an increase in insulin secretion, a higher risk of diabetes, and disrupted calcium signaling. Insomnia-associated genotypic differences were highly concentrated within genes involved in neural function. The most significant SNPs resided in ROR1 and PLCB1, genes known to be involved in bipolar disorder and schizophrenia, respectively. Putative enhancers, as indicated by the histone mark H3K4me1, were discovered within both genes near the significant SNPs. In neuronal cells, the enhancers were bound by PAX6, a neural transcription factor that is essential for central nervous system development. Open chromatin signatures were found on the enhancers in human pancreas, a tissue where PAX6 is known to play a role in insulin secretion. In PLCB1, CTCF was found to bind downstream of the enhancer and interact with PAX6, suggesting that it can probably inhibit gene activation by PAX6. PLCB4, a circadian gene that is closely located downstream of PLCB1, was identified as a candidate target gene. Hence, dysregulation of ROR1, PLCB1, or PLCB4 by PAX6 and CTCF may be one mechanism that links neural and pancreatic dysfunction not only in insomnia but also in the relevant psychiatric disorders that are accompanied with circadian rhythm disruption and metabolic syndrome.
authors.affiliation: Division of Bio-Medical Informatics, National Institute of Health, Korea Centers for Disease Control and Prevention, Choongchung-Buk-do, Korea.
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Ban
authors.forename: Sang Cheol
authors.initials: SC
authors.lastname: Kim
authors.forename: Jungmin
authors.initials: J
authors.lastname: Seo
authors.forename: Ho-Bum
authors.initials: HB
authors.lastname: Kang
authors.forename: Jung Kyoon
authors.initials: JK
authors.lastname: Choi
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008875:Middle Aged; D054799:Phospholipase C beta / Q000235:genetics; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics; D012890:Sleep; D007319:Sleep Initiation and Maintenance Disorders / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D002843:Chromatin; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C518033:PLCB1 protein, human; D054799:Phospholipase C beta