Variations in circadian genes and individual nocturnal symptoms of insomnia. The HUNT study

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 (<i>PER1, 2, 3, CRY1, 2, TIMELESS, CLOCK, REV-ERBα, ARNTL</i>) for differences among symptoms subgroups. Twenty-five SNPs showed significant p-values and supportive odds-ratios. All significant SNPs in <i>PER3</i> were associated with reporting all three symptoms simultaneously. SNPs in <i>CRY</i> genes were associated with terminal insomnia alone or in combination with other symptoms. Genes <i>PER1</i> 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.

失眠是一种以三种夜间症状为特征的病症：睡眠启动困难、睡眠维持障碍以及清晨早醒（终末性失眠）。受累个体可出现其中一种或多种症状。多项研究表明，失眠具有中度遗传度，且三种失眠症状的替代表型展现出不同的遗传度。这提示失眠的不同夜间症状可能源自不同的遗传与生物学背景。节律基因（circadian genes）是解释这些差异的理想候选靶点，因为它们调控包括睡眠在内的多项生理功能的节律性。来自动物与人类研究的证据表明，节律基因可能参与包括失眠在内的睡眠障碍发生过程。本研究借助北特伦德拉格健康研究3期（HUNT3研究，样本量N=50807）的数据，探究了节律基因中的单核苷酸多态性（Single Nucleotide Polymorphisms, SNPs）与失眠各单项症状及其组合的关联。共有6029名参与者提供了关于睡眠启动型失眠、睡眠维持型失眠以及终末性失眠的相关信息。对上述任一症状相关问题回答“每周数次”的参与者被划分为病例组（N=3577），并根据可能的症状组合被分为7个亚组。对照组（N=2452）的参与者对所有睡眠相关问题均回答“从不/极少”。本研究采用多项回归分析，对9个节律基因（PER1、PER2、PER3、CRY1、CRY2、TIMELESS、CLOCK、REV-ERBα、ARNTL）的73个单核苷酸多态性进行分析，以探究各症状亚组间的差异。共有25个单核苷酸多态性呈现出具有统计学意义的P值以及具有参考价值的比值比。所有在PER3基因中检出的显著单核苷酸多态性均与同时报告三种失眠症状的情况相关。CRY家族基因的单核苷酸多态性则与单纯终末性失眠，或终末性失眠合并其他失眠症状的情况相关。PER1与PER2基因的单核苷酸多态性主要与睡眠维持型失眠相关。然而，经过多重统计检验的错误发现率（False Discovery Rate, FDR）校正后，所有单核苷酸多态性均不再具有统计学显著性。综上，尽管经错误发现率校正后无单核苷酸多态性仍保持显著性，但部分基因在特定失眠症状上的聚集性提示，有必要针对这些关联开展进一步研究。