Genetic polymorphisms associated with sleep-related phenotypes; relationships with individual nocturnal symptoms of insomnia in the HUNT study.

BACKGROUND: In recent years, several GWAS (genome wide association studies) of sleep-related traits have identified a number of SNPs (single nucleotides polymorphism) but their relationships with symptoms of insomnia are not known. The aim of this study was to investigate whether SNPs, previously reported in association with sleep-related phenotypes, are associated with individual symptoms of insomnia. METHODS: We selected participants from the HUNT study (Norway) who reported at least one symptom of insomnia consisting of sleep onset, maintenance or early morning awakening difficulties, (cases, N = 2563) compared to participants who presented no symptoms at all (controls, N = 3665). Cases were further divided in seven subgroups according to different combinations of these three symptoms. We used multinomial logistic regressions to test the association among different patterns of symptoms and 59 SNPs identified in past GWAS studies. RESULTS: Although 16 SNPS were significantly associated (p < 0.05) with at least one symptom subgroup, none of the investigated SNPs remained significant after correction for multiple testing using the false discovery rate (FDR) method. CONCLUSIONS: SNPs associated with sleep-related traits do not replicate on any pattern of insomnia symptoms after multiple tests correction. However, correction in this case may be overly conservative.

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 (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.

Differences in anxiety levels among symptoms of insomnia. The HUNT study.

OBJECTIVES: This study aim is to compare anxiety levels among individuals experiencing different symptoms of insomnia. DESIGN: Case-control study. SETTING: The Nord-Trøndelag Health Study (the HUNT3 study, Norway). PARTICIPANTS: Of the 50,802 individuals taking part in the HUNT3 study, the current sample comprised 7933 individuals, including 4317 cases with insomnia and 3616 controls. MEASUREMENTS: Symptoms of anxiety were assessed using Hospital Anxiety and Depression Scale, whereas insomnia symptoms were assessed according to the core Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, nocturnal symptoms. Anxiety levels of the 4317 individuals reporting at least 1 insomnia symptom were compared with the 3616 controls reporting no symptoms. Level of anxiety among participants experiencing combinations of insomnia symptoms was also investigated. RESULTS: Anxiety levels were significantly higher in individuals reporting insomnia symptoms (M = 2.5, SD = 2.4) compared to controls (5.5, SD = 3.7, P < .001). Anxiety levels also differed significantly between different insomnia symptoms (P < .001). Participants reporting all 3 insomnia symptoms had the highest anxiety score (M = 6.8, SD = 4.3), followed in decreasing order by sleep onset insomnia with terminal insomnia (M = 6.7, SD = 4.0), sleep onset insomnia with sleep maintenance insomnia (M = 6.3, SD = 3.8), sleep onset insomnia only (M = 5.8, SD = 3.7), sleep maintenance insomnia with terminal insomnia (M = 5.6, SD = SD = 3.4), terminal insomnia (M = 5.2, SD = 3.4), and sleep maintenance insomnia only (M = 4.5, SD = 3). CONCLUSIONS: Difficulties initiating sleep, both alone and in combination with 1 or 2 of the other symptoms, seem to play a key role in rising anxiety levels.