a Department of Research and Development (AFFU) , Norwegian University of Science and Technology (NTNU) , Trondheim , Norway.
b Department of Mental health , Norwegian University of Science and Technology (NTNU) , Trondheim , Norway.
Chronobiol Int. 2019 May;36(5):681-688. doi: 10.1080/07420528.2019.1582540. Epub 2019 Mar 12.
Insomnia is a condition characterized by three nocturnal symptoms: problems with sleep onset or maintenance and early morning awakenings (terminal insomnia). Affected individuals may present one or more of these symptoms. Several studies have shown that insomnia is moderately heritable and that proxy phenotypes for the three insomnia symptoms show different heritabilities. This suggests that different nocturnal symptoms of insomnia may arise from different genetic and biological backgrounds. Circadian genes are good candidates to account for these differences as they regulate the periodicity of several physiological functions including sleep. Evidence from studies in animals and humans have suggested that circadian genes might be involved in sleep disturbances such as insomnia. In this study, we investigated the association between Single Nucleotide Polymorphisms (SNPs) in circadian genes and individual symptoms of insomnia and their combinations using data from the Nord-Trøndelag Health Study 3 (the HUNT3 study, N = 50807). Participants (N = 6029) provided information about sleep onset insomnia, maintenance insomnia, and terminal insomnia. Participants who responded "several times a week" to at least one question regarding the mentioned symptoms were classified as cases (N = 3577) and categorized in seven subgroups according to possible symptom combinations. Controls (N = 2452) answered "Never/Seldom" to all sleep-related questions. Using multinomial regression, we assessed 73 SNPs in nine circadian genes (PER1, 2, 3, CRY1, 2, TIMELESS, CLOCK, REV-ERBα, ARNTL) for differences among symptoms subgroups. Twenty-five SNPs showed significant p-values and supportive odds-ratios. All significant SNPs in PER3 were associated with reporting all three symptoms simultaneously. SNPs in CRY genes were associated with terminal insomnia alone or in combination with other symptoms. Genes PER1 and two were mostly associated with sleep maintenance insomnia. However, none of the SNPs remained significant after False Discovery Rate (FDR) correction for multiple statistical testing. In conclusion, even though none of the SNPs remained significant after FDR correction, the clustering of some genes around specific symptoms points to the need for additional research on these relationships.
入睡或维持睡眠困难和清晨早醒（终末失眠）。受影响的个体可能表现出这些症状中的一种或多种。几项研究表明，失眠具有中等程度的遗传性，三种失眠症状的替代表型显示出不同的遗传性。这表明失眠的不同夜间症状可能源于不同的遗传和生物学背景。生物钟基因是解释这些差异的良好候选者，因为它们调节包括睡眠在内的多种生理功能的周期性。动物和人类研究的证据表明，生物钟基因可能与失眠等睡眠障碍有关。在这项研究中，我们使用来自挪威特隆赫姆健康研究 3 号（HUNT3 研究，N=50807）的数据，调查了生物钟基因的单核苷酸多态性（SNP）与个体失眠症状及其组合之间的关联。参与者（N=6029）提供了关于入睡性失眠、维持性失眠和终末性失眠的信息。对至少一个关于上述症状的问题回答“每周几次”的参与者被归类为病例（N=3577），并根据可能的症状组合分为七个亚组。对照组（N=2452）对所有与睡眠相关的问题均回答“从不/很少”。我们使用多项回归分析了九个生物钟基因（PER1、2、3、CRY1、2、TIMELSS、CLOCK、REV-ERBα、ARNTL）中的 73 个 SNP，以评估它们在症状亚组之间的差异。25 个 SNP 显示出显著的 p 值和支持的比值比。PER3 中的所有显著 SNP 均与同时报告所有三种症状相关。CRY 基因的 SNP 与终末性失眠有关，或与其他症状同时存在。PER1 和 PER2 基因主要与维持性失眠有关。然而，在进行多重统计检验的错误发现率（FDR）校正后，没有一个 SNP 仍然具有统计学意义。总之，尽管在 FDR 校正后没有 SNP 仍然具有统计学意义，但一些基因围绕特定症状聚类表明需要进一步研究这些关系。
