Genetic and Metabolic Characterization of Insomnia

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.

据报道，慢性失眠在成年人群中的患病率达10%~15%。然而，目前学界对失眠的遗传学基础与代谢调控机制仍知之甚少。本研究纳入10038名韩国受试者，其基因型此前已完成全基因组规模的分型检测。其中约16.5%的受试者自述存在失眠症状，且呈现出显著的代谢异常特征：包括胰岛素分泌水平升高、糖尿病患病风险增加以及钙信号通路紊乱。与失眠相关的基因型差异高度富集于参与神经功能调控的基因中。本研究鉴定出的最显著单核苷酸多态性（Single Nucleotide Polymorphisms, SNPs）位点位于ROR1与PLCB1基因内，这两个基因此前已被证实分别与双相情感障碍和精神分裂症相关。研究人员在上述两个基因内显著SNPs位点的邻近区域，发现了经组蛋白标记H3K4me1提示的潜在增强子序列。在神经元细胞中，这些增强子可与转录因子PAX6结合；PAX6作为一种神经转录因子，对中枢神经系统的发育至关重要。在人类胰腺组织的增强子区域内，检测到开放染色质特征，而PAX6在胰腺组织中已知可参与胰岛素分泌的调控过程。在PLCB1基因区域内，研究发现CCCTC结合因子（CCCTC-binding factor, CTCF）可结合增强子的下游区域，并与PAX6发生相互作用，提示其可能抑制PAX6介导的基因激活。位于PLCB1下游紧邻区域的昼夜节律基因PLCB4，被鉴定为潜在的靶基因。综上，PAX6与CTCF对ROR1、PLCB1或PLCB4的调控异常，可能是连接神经与胰腺功能紊乱的潜在机制之一：该机制不仅参与失眠的发病进程，还可作用于伴随昼夜节律紊乱与代谢综合征的相关精神疾病。