Annemarie I. Luik

Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank.

Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and chronic disease. Here we perform a genome-wide association study of self-reported chronotype within the UK Biobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian clock machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or light-sensing pathways. Pathway analyses highlight central nervous and ocular systems and fear-response-related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans but also expose the influence of circadian characteristics over human health and life-history variables such as educational attainment.

Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits

Chronic sleep disturbances, associated with cardiometabolic diseases, psychiatric disorders and all-cause mortality, affect 25–30% of adults worldwide. Although environmental factors contribute substantially to self-reported habitual sleep duration and disruption, these traits are heritable and identification of the genes involved should improve understanding of sleep, mechanisms linking sleep to disease and development of new therapies. We report single- and multiple-trait genome-wide association analyses of self-reported sleep duration, insomnia symptoms and excessive daytime sleepiness in the UK Biobank (n = 112,586). We discover loci associated with insomnia symptoms (near MEIS1, TMEM132E, CYCL1 and TGFBI in females and WDR27 in males), excessive daytime sleepiness (near AR–OPHN1) and a composite sleep trait (near PATJ (INADL) and HCRTR2) and replicate a locus associated with sleep duration (at PAX8). We also observe genetic correlation between longer sleep duration and schizophrenia risk (rg = 0.29, P = 1.90 × 10−13) and between increased levels of excessive daytime sleepiness and increased measures for adiposity traits (body mass index (BMI): rg = 0.20, P = 3.12 × 10−9; waist circumference: rg = 0.20, P = 2.12 × 10−7).

Fragmentation and Stability of Circadian Activity Rhythms Predict Mortality The Rotterdam Study

Circadian rhythms and sleep patterns change as people age. Little is known about the associations between circadian rhythms and mortality rates. We investigated whether 24-hour activity rhythms and sleep characteristics independently predicted mortality. Actigraphy was used to determine the stability and fragmentation of the 24-hour activity rhythm in 1,734 persons (aged 45-98 years) from the Rotterdam Study (2004-2013). Sleep was assessed objectively using actigraphy and subjectively using sleep diaries to estimate sleep duration, sleep onset latency, and waking after sleep onset. The mean follow-up time was 7.3 years; 154 participants (8.9%) died. Sleep measures were not related to mortality after adjustment for health parameters. In contrast, a more stable 24-hour activity rhythm was associated with a lower mortality risk (per 1 standard deviation, hazard ratio = 0.83, 95% confidence interval: 0.71, 0.96), and a more fragmented rhythm was associated with a higher mortality risk (per 1 standard deviation, hazard ratio = 1.22, 95% confidence interval: 1.04, 1.44). Low stability and high fragmentation of the 24-hour activity rhythm predicted all-cause mortality, whereas estimates from actigraphy and sleep diaries did not. Disturbed circadian activity rhythms reflect age-related alterations in the biological clock and could be an indicator of disease.

The effects of improving sleep on mental health (OASIS): a randomised controlled trial with mediation analysis

Summary Background Sleep difficulties might be a contributory causal factor in the occurrence of mental health problems. If this is true, improving sleep should benefit psychological health. We aimed to determine whether treating insomnia leads to a reduction in paranoia and hallucinations. Methods We did this single-blind, randomised controlled trial (OASIS) at 26 UK universities. University students with insomnia were randomly assigned (1:1) with simple randomisation to receive digital cognitive behavioural therapy (CBT) for insomnia or usual care, and the research team were masked to the treatment. Online assessments took place at weeks 0, 3, 10 (end of therapy), and 22. The primary outcome measures were for insomnia, paranoia, and hallucinatory experiences. We did intention-to-treat analyses. The trial is registered with the ISRCTN registry, number ISRCTN61272251. Findings Between March 5, 2015, and Feb 17, 2016, we randomly assigned 3755 participants to receive digital CBT for insomnia (n=1891) or usual practice (n=1864). Compared with usual practice, the sleep intervention at 10 weeks reduced insomnia (adjusted difference 4·78, 95% CI 4·29 to 5·26, Cohens d=1·11; p<0·0001), paranoia (−2·22, −2·98 to −1·45, Cohens d=0·19; p<0·0001), and hallucinations (−1·58, −1·98 to −1·18, Cohens d=0·24; p<0·0001). Insomnia was a mediator of change in paranoia and hallucinations. No adverse events were reported. Interpretation To our knowledge, this is the largest randomised controlled trial of a psychological intervention for a mental health problem. It provides strong evidence that insomnia is a causal factor in the occurrence of psychotic experiences and other mental health problems. Whether the results generalise beyond a student population requires testing. The treatment of disrupted sleep might require a higher priority in mental health provision. Funding Wellcome Trust.

Sleep and Productivity Benefits of Digital Cognitive Behavioral Therapy for Insomnia: A Randomized Controlled Trial Conducted in the Workplace Environment.

Objective: Evaluating digital cognitive behavioral therapy (dCBT) for insomnia in a workplace environment. Methods: Within a randomized controlled trial in a Fortune 500 company, we randomized 270 self-identified poor sleepers [180 M/90 F: mean age 33.6 years (23 to 56 years)] to dCBT (nu200a=u200a135) or waiting list (WL, nu200a=u200a135). dCBT comprised six online sessions delivered by an animated therapist. Major assessments were at baseline and posttreatment. Results: Sleep Condition Indicator (SCI) scores were significantly higher for the dCBT group [interaction term: F (1,485)u200a=u200a15.63, Pu200a<u200a0.0001], representing Cohens d of 1.10 following dCBT (du200a=u200a0.34 for WL). On the Work Productivity and Impairment questionnaire, “presenteeism” demonstrated significant improvements following dCBT [F(1,485)u200a=u200a10.99, Pu200a=u200a0.001: du200a=u200a0.64 for dCBT, du200a=u200a0.09 for WL]. Effects for “abseenteeism” failed to reach statistical significance (Pu200a=u200a0.101). Conclusions: dCBT is effective in improving sleep and work-based productivity in adults with insomnia.

Genetic variants in RBFOX3 are associated with sleep latency

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2u2009572u2009737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10−08, 6.59 × 10−08 and 9.17 × 10−08). These SNPs were replicated in up to 12 independent populations including 30u2009377 individuals (P-values=1.5 × 10−02, 7.0 × 10−03 and 2.5 × 10−03; combined meta-analysis P-values=5.5 × 10−07, 5.4 × 10−07 and 1.0 × 10−07). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10−316) and the central nervous system (P-value=7.5 × 10−321). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values<2.9 × 10−11) that are crucial in triggering the onset of sleep. To conclude, in this first large-scale GWAS of sleep latency we report a novel association of variants in RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the involvement of RBFOX3 with sleep latency.

Digital Cognitive Behavioural Therapy for Insomnia versus sleep hygiene education: the impact of improved sleep on functional health, quality of life and psychological well-being. Study protocol for a randomised controlled trial

BackgroundPrevious research has demonstrated that digital CBT (dCBT), delivered via the Internet, is a scalable and effective intervention for treating insomnia in otherwise healthy adults and leads to significant improvements in primary outcomes relating to sleep. The majority of people with insomnia, however, seek help because of the functional impact and daytime consequences of poor sleep, not because of sleep discontinuity per se. Although some secondary analyses suggest that dCBT may have wider health benefits, no adequately powered study has investigated these as a primary endpoint. This study specifically aims to investigate the impact of dCBT for insomnia upon health and well-being, and will investigate sleep-related changes as mediating factors.Methods/designWe propose a pragmatic, parallel-group, randomised controlled trial of 1000 community participants meeting criteria for insomnia disorder. In the DIALS trial (Digital Insomnia therapy to Assist your Life as well as your Sleep), participants will be randomised to dCBT delivered using web and/or mobile channels (in addition to treatment as usual (TAU)) or to sleep hygiene education (SHE), comprising a website plus a downloadable booklet (in addition to TAU). Online assessments will take place at 0 (baseline), 4 (mid-treatment), 8 (post-treatment), and 24 (follow-up) weeks. At week 25 all participants allocated to SHE will be offered dCBT, at which point the controlled element of the trial will be complete. Naturalistic follow-up will be invited at weeks 36 and 48. Primary outcomes are functional health and well-being at 8xa0weeks. Secondary outcomes are mood, fatigue, sleepiness, cognitive function, productivity and social functioning. All main analyses will be carried out at the end of the final controlled follow-up assessments and will be based on the intention-to-treat principle. Further analyses will determine whether observed changes in functional health and well-being are mediated by changes in sleep. The trial is funded by Big Health Ltd.DiscussionThis study will be the first large-scale, specifically designed investigation of the health and well-being benefits of CBT for insomnia, and the first examination of the association between CBT-mediated sleep improvement and health status.Trial registrationISRCTN60530898.

The Pros and Cons of Getting Engaged in an Online Social Community Embedded Within Digital Cognitive Behavioral Therapy for Insomnia: Survey Among Users.

Background Sleepio is a proven digital sleep improvement program based on cognitive behavioral therapy techniques. Users have the option to join an online community that includes weekly expert discussions, peer-to-peer discussion forums, and personal message walls. Objective The aim of this study was to conduct an online survey to (1) explore the reasons for deciding to engage with the Sleepio online community, (2) explore the potential benefits arising from engagement with the online community, and (3) identify and describe any problematic issues related to use of the online community. Methods We developed an online survey and posted an invitation to the community discussion forum inviting users to participate. In addition, we sent an email invitation to 970 individuals who had previously or were currently working through the Sleepio program to participate in this study. Results In total, 100 respondents (70/100, 70% female; mean age 51 years, range 26–82 years) completed the online survey. Most respondents had started Sleepio with chronic sleep problems (59/100, 59% up to 10 years; 35/100, 35% >10 years) and had actively engaged with the online community (85/100, 85%) had made a discussion or wall post). At the time of the survey, respondents had used Sleepio for a median of 12 weeks (range from 3 weeks to 2 years). We analyzed responses to the open-ended questions using thematic analysis. This analysis revealed 5 initial drivers for engagement: (1) the desire to connect with people facing similar issues, (2) seeking personalized advice, (3) curiosity, (4) being invited by other members, and (5) wanting to use all available sleep improvement tools. Advantages of engagement included access to continuous support, a reduced sense of isolation, being part of a nonjudgmental community, personalized advice, positive comparisons with others, encouragement to keep going, and altruism. We found 5 potential disadvantages: design and navigation issues, uncertain quality of user-generated content, negative comparisons with others, excessive time commitments, and data privacy concerns. Participants related their community experiences to engagement with the Sleepio program, with many stating it had supported their efforts to improve their sleep, as well as helping with adherence and commitment to the program. Despite some concerns, members regarded the Sleepio community as a valuable resource. Conclusions Online communities may be a useful means through which to support long-term engagement with Web-based therapy for insomnia.

Psychometric properties of the Sleep Condition Indicator and Insomnia Severity Index in the evaluation of insomnia disorder

OBJECTIVEnThe Sleep Condition Indicator (SCI) and Insomnia Severity Index (ISI) are commonly used instruments to assess insomnia. We evaluated their psychometric properties, particularly their discriminant validity against structured clinical interview (according to DSM-5 and ICSD-3), and their concurrent validity with measures of sleep and daytime functioning.nnnMETHODSnA total of 158 young adults, 16% of whom were diagnosed with DSM-5 insomnia disorder and 13% with ICSD-3 Chronic Insomnia by structured interview, completed the ISI and SCI twice in 7-14 days, in addition to measures of sleep and daytime function.nnnRESULTSnThe Chinese version of the SCI was validated with good psychometric properties (ICCxa0=xa00.882). A cutoff of ≥8 on the ISI, ≤5 on the SCI short form, and ≤21 on the SCI achieved high discriminant validity (AUCxa0>xa00.85) in identifying individuals with insomnia based on both DSM-5 and ICSD-3 criteria. The SCI and ISI had comparable associations with subjective (0.18xa0<xa0rxa0<xa00.51) and actigraphic sleep (0.31xa0<xa0rxa0<xa00.43) and daytime functioning (0.34xa0<xa0rxa0<xa00.53).nnnCONCLUSIONnThe SCI, SCI short form, and ISI were found to correctly identify individuals with DSM-5- and ICSD-3-defined insomnia disorder. Moreover, they showed good concordance with measures of daytime dysfunction, as well as subjective and objective sleep. The SCI and ISI are recommended for use in clinical and research settings.

Sleep and cognitive performance: cross-sectional associations in the UK Biobank.

OBJECTIVEnThe relationship between insomnia symptoms and cognitive performance is unclear, particularly at the population level. We conducted the largest examination of this association to date through analysis of the UK Biobank, a large population-based sample of adults aged 40-69 years. We also sought to determine associations between cognitive performance and self-reported chronotype, sleep medication use and sleep duration.nnnMETHODSnThis cross-sectional, population-based study involved 477,529 participants, comprising 133,314 patients with frequent insomnia symptoms (age: 57.4xa0±xa07.7 years; 62.1% female) and 344,215 controls without insomnia symptoms (age: 56.1xa0±xa08.2 years; 52.0% female). Cognitive performance was assessed by a touchscreen test battery probing reasoning, basic reaction time, numeric memory, visual memory, and prospective memory. Adjusted models included relevant demographic, clinical, and sleep variables.nnnRESULTSnFrequent insomnia symptoms were associated with cognitive impairment in unadjusted models; however, these effects were reversed after full adjustment, leaving those with frequent insomnia symptoms showing statistically better cognitive performance over those without. Relative to intermediate chronotype, evening chronotype was associated with superior task performance, while morning chronotype was associated with the poorest performance. Sleep medication use and both long (>9xa0h) and short (<7xa0h) sleep durations were associated with impaired performance.nnnCONCLUSIONSnOur results suggest that after adjustment for potential confounding variables, frequent insomnia symptoms may be associated with a small statistical advantage, which is unlikely to be clinically meaningful, on simple neurocognitive tasks. Further work is required to examine the mechanistic underpinnings of an apparent evening chronotype advantage in cognitive performance and the impairment associated with morning chronotype, sleep medication use, and sleep duration extremes.