Genetic and psychopathological characteristics of patterns of nocturnal symptoms of insomnia - An epidemiological perspective using data from the HUNT3 Study
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Summary Background and objectives Chronic insomnia is a sleep disorder characterized by diurnal and nocturnal symptoms. The night-time disturbances specified by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) are: difficulties in falling asleep (sleep onset insomnia), frequent awakenings during the night (maintenance insomnia) and early morning awakenings (terminal insomnia). One aspect often ignored in insomnia research is that these symptoms may appear in different combinations. Hypothetically, although related, these symptoms may have different characteristics and causes. Two widely investigated aspects of insomnia are its relationship with other psychological disorders, like anxiety and depression and their genetic background. Unfortunately, neither of these aspects has been studied considering nocturnal symptoms of insomnia separately. The aim of this PhD project was to investigate whether the nocturnal symptoms of insomnia should be considered equivalent manifestations of the same disorder or separate entities with individual genetic backgrounds and relationships to psychopathological symptoms. Material and methods The individuals selected to be included in all four studies described in this thesis were selected among individuals who participated in the third round of the Nord-Trøndelag Health Study (the HUNT3 study, Norway). Information about insomnia, psychological health and genetic variations for the participants were obtained from the HUNT data and biobank. In each study, the presence of each nocturnal symptom of insomnia was evaluated using a Likert-like scale (“Never”, “Sometimes”, “Several times a week”). Participants who answered “Several times a week” to at least one question were selected as cases, while those who answered “Never” to all question were defined as controls. For the first two studies, we selected 6029 participants with genetic data, 3577 cases and 2452 controls. In study 3 and 4 we had data for 7933 individuals, 4317 cases and 3616 controls. In study 1, multinomial regression was used to assess the association among all seven possible combinations of symptoms of insomnia and 73 single nucleotide polymorphisms (SNPs) selected on nine core circadian genes (PER1, 2, 3, CRY1, 2, TIMELESS, CLOCK, REV-ERBα, ARNTL). In study 2, multinomial regression was used to test the associations among all possible patterns of insomnia symptoms and 59 SNPs previously reported as associated with sleep traits. In study 3 we reported means scores for the anxiety subscale of the Hospital Anxiety and Depression Scale (HADS) among the patters of symptoms of insomnia and compared them using ANOVA. Finally, using the same methodology of study 3 in study 4 we focused on differences on the depression subscale of HADS among the different patterns of symptoms. Results In study 1, 25 of the SNPs in circadian genes were significantly associated with patterns of symptoms of insomnia. We observed that the majority of SNPs on gene PER3 were associated with reporting all three symptoms, those on gene CRY with early morning awakenings and those on ARNTL with sleep onset insomnia. Nevertheless, no association remained significant after applying correction for multiple testing. In study 2, 16 SNPs selected from previous studies on sleep traits were associated with several combinations of symptoms of insomnia. However, none of them remained significant after applying correction for multiple statistical testing. In study 3, mean HADS-A score was statistically different among several insomnia symptoms (p < .001). Participants reporting sleep maintenance insomnia only (M = 4.5, SD = 3) had the lowest mean anxiety score while those experiencing all three symptoms had the highest (M = 6.8, SD = 4.3). Persons reporting only sleep onset insomnia had the highest mean HADS-A score among respondents with just one symptom (M = 5.8, SD = 3.7). Overall, difficulties falling asleep seemed to play a decisive role in rising HADS-A levels. In study 4, we found only moderate differences in HADS-D levels among patters of symptoms of insomnia. Persons who reported all three symptoms of insomnia had the highest HADS-D mean score (M=5.2, SD=3.6), however the mean did not differ significantly from those who experienced sleep onset insomnia combined with terminal insomnia (M=5.4, SD=3.4). Correspondingly, participants who reported only sleep maintenance insomnia had the lowest mean score (M=3.4, SD=2.9). Conclusions Anxiety levels as measured by HADS-A were the only significant and relevant element that differed among patterns of symptoms of insomnia. In particular, sleep onset insomnia was the symptom that displayed the highest levels of anxiety, both alone and when occurring with other symptoms. Even if we did not find any statistically significant association among the phenotypes and the genetic markers we selected, we cannot exclude that symptoms of insomnia may have different genetic backgrounds. Despite the lack of statistical significance, the results may be indicative of the presence of influence of the investigated genes on different symptoms. The assumption arises from the almost exclusive association of some genes (PER3, CRY1, CRY2 and ARNTL) with specific symptoms and the plausible biological role of some genes already associated with sleep phenotypes. Differences in depression levels were not clinically significant among the symptoms but measuring tool with higher precision than HADS-D may reveal these differences in future studies.
Has partsPaper 1: Bragantini, Daniela; Sivertsen, Børge; Gehrman, Philip; Lydersen, Stian; Guzey, Ismail Cuneyt. Variations in circadian genes and individual nocturnal symptoms of insomnia. The HUNT study. Chronobiology International 2019 ;Volum 36.(5) s. 681-688 https://doi.org/10.1080/07420528.2019.1582540
Paper 2: Bragantini, Daniela; Sivertsen, Børge; Gehrman, Philip; Lydersen, Stian; Guzey, Ismail Cuneyt. Genetic polymorphisms associated with sleep-related phenotypes; relationships with individual nocturnal symptoms of insomnia in the HUNT study. BMC Medical Genetics 2019 ;Volum 20. s. 1-7 https://doi.org/10.1186/s12881-019-0916-6 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/)
Paper 3: Bragantini, Daniela; Sivertsen, Børge; Gehrman, Philip; Lydersen, Stian; Guzey, Ismail Cuneyt. Differences in anxiety levels among symptoms of insomnia. The HUNT study. Sleep Health 2019 ;Volum 5.(4) s. 370-375 https://doi.org/10.1016/j.sleh.2019.01.002
Paper 4: Bragantini D, Sivertsen B, Gehrman P, Lydersen S, Güzey IC. Epidemiological differences in levels of depressive signs among nocturnal symptoms of insomnia; results from the HUNT study. Sleep science and practice. 2020; 4(7). https://doi.org/10.1186/s41606-020-00043-1 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/)