Associations of a multidimensional polygenic sleep health score and a sleep lifestyle index on health outcomes and their interaction in a clinical biobank.

Sleep is a complex behavior regulated by genetic and environmental factors, and is known to influence health outcomes. However, the effect of multidimensional sleep encompassing several sleep dimensions on diseases has yet to be fully elucidated. Using the Mass General Brigham Biobank, we aimed to examine the association of multidimensional sleep with health outcomes and investigate whether sleep behaviors modulate genetic predisposition to unfavorable sleep on mental health outcomes. First, we generated a Polygenic Sleep Health Score using previously identified single nucleotide polymorphisms for sleep health and constructed a Sleep Lifestyle Index using data from self-reported sleep questions and electronic health records; second, we performed phenome-wide association analyses between these indexes and clinical phenotypes; and third, we analyzed the interaction between the indexes on prevalent mental health outcomes. Fifteen thousand eight hundred and eighty-four participants were included in the analysis (mean age 54.4; 58.6% female). The Polygenic Sleep Health Score was associated with the Sleep Lifestyle Index (ß=0.050, 95%CI=0.032, 0.068) and with 114 disease outcomes spanning 12 disease groups, including obesity, sleep, and substance use disease outcomes (p<3.3×10-5). The Sleep Lifestyle Index was associated with 458 disease outcomes spanning 17 groups, including sleep, mood, and anxiety disease outcomes (p<5.1×10-5). No interactions were found between the indexes on prevalent mental health outcomes. These findings suggest that favorable sleep behaviors and genetic predisposition to healthy sleep may independently be protective of disease outcomes. This work provides novel insights into the role of multidimensional sleep on population health and highlights the need to develop prevention strategies focused on healthy sleep habits.

Genome-wide association analysis of composite sleep health scores in 413,904 individuals.

Recent genome-wide association studies (GWASs) of several individual sleep traits have identified hundreds of genetic loci, suggesting diverse mechanisms. Moreover, sleep traits are moderately correlated, and together may provide a more complete picture of sleep health, while also illuminating distinct domains. Here we construct novel sleep health scores (SHSs) incorporating five core self-report measures: sleep duration, insomnia symptoms, chronotype, snoring, and daytime sleepiness, using additive (SHS-ADD) and five principal components-based (SHS-PCs) approaches. GWASs of these six SHSs identify 28 significant novel loci adjusting for multiple testing on six traits (p<8.3e-9), along with 341 previously reported loci (p<5e-08). The heritability of the first three SHS-PCs equals or exceeds that of SHS-ADD (SNP-h2=0.094), while revealing sleep-domain-specific genetic discoveries. Significant loci enrich in multiple brain tissues and in metabolic and neuronal pathways. Post GWAS analyses uncover novel genetic mechanisms underlying sleep health and reveal connections to behavioral, psychological, and cardiometabolic traits.

The Role of Circadian Rhythms and Sleep in Anorexia Nervosa.

Importance: Observational studies have associated anorexia nervosa with circadian rhythms and sleep traits. However, the direction of causality and the extent of confounding by psychosocial comorbidities in these associations are unknown. Objectives: To investigate the association between anorexia nervosa and circadian and sleep traits through mendelian randomization and to test the associations between a polygenic risk score (PRS) for anorexia nervosa and sleep disorders in a clinical biobank. Design, Setting, and Participants: This genetic association study used bidirectional 2-sample mendelian randomization with summary-level genetic associations between anorexia nervosa (from the Psychiatric Genomics Consortium) and chronotype and sleep traits (primarily from the UK Biobank). The inverse-variance weighted method, in addition to other sensitivity approaches, was used. From the clinical Mass General Brigham (MGB) Biobank (n = 47 082), a PRS for anorexia nervosa was calculated for each patient and associations were tested with prevalent sleep disorders derived from electronic health records. Patients were of European ancestry. All analyses were performed between February and August 2023. Exposures: Genetic instruments for anorexia nervosa, chronotype, daytime napping, daytime sleepiness, insomnia, and sleep duration. Main Outcomes and Measures: Chronotype, sleep traits, risk of anorexia nervosa, and sleep disorders derived from a clinical biobank. Results: The anorexia nervosa genome-wide association study included 16 992 cases (87.7%-97.4% female) and 55 525 controls (49.6%-63.4% female). Genetic liability for anorexia nervosa was associated with a more morning chronotype (ß = 0.039; 95% CI, 0.006-0.072), and conversely, genetic liability for morning chronotype was associated with increased risk of anorexia nervosa (ß = 0.178; 95% CI, 0.042-0.315). Associations were robust in sensitivity and secondary analyses. Genetic liability for insomnia was associated with increased risk of anorexia nervosa (ß = 0.369; 95% CI, 0.073-0.666); however, sensitivity analyses indicated bias due to horizontal pleiotropy. The MGB Biobank analysis included 47 082 participants with a mean (SD) age of 60.4 (17.0) years and 25 318 (53.8%) were female. A PRS for anorexia nervosa was associated with organic or persistent insomnia in the MGB Biobank (odds ratio, 1.10; 95% CI, 1.03-1.17). No associations were evident for anorexia nervosa with other sleep traits. Conclusions and Relevance: The results of this study suggest that in contrast to other metabo-psychiatric diseases, anorexia nervosa is a morningness eating disorder and further corroborate findings implicating insomnia in anorexia nervosa. Future studies in diverse populations and with subtypes of anorexia nervosa are warranted.

Selection of genetic instruments in Mendelian randomisation studies of sleep traits.

This review explores the criteria used for the selection of genetic instruments of sleep traits in the context of Mendelian randomisation studies. This work was motivated by the fact that instrument selection is the most important decision when designing a Mendelian randomisation study. As far as we are aware, no review has sought to address this to date, even though the number of these studies is growing rapidly. The review is divided into the following sections which are essential for genetic instrument selection: 1) Single-gene region vs polygenic analysis; 2) Polygenic analysis: biologically-vs statistically-driven approaches; 3) P-value; 4) Linkage disequilibrium clumping; 5) Sample overlap; 6) Type of exposure; 7) Total (R2) and average strength (F-statistic) metrics; 8) Number of single-nucleotide polymorphisms; 9) Minor allele frequency and palindromic variants; 10) Confounding. Our main aim is to discuss how instrumental choice impacts analysis and compare the strategies that Mendelian randomisation studies of sleep traits have used. We hope that our review will enable more researchers to take a more considered approach when selecting genetic instruments for sleep exposures.

Is there an association between daytime napping, cognitive function, and brain volume? A Mendelian randomization study in the UK Biobank.

OBJECTIVES: Daytime napping has been associated with cognitive function and brain health in observational studies. However, it remains elusive whether these associations are causal. Using Mendelian randomization, we studied the relationship between habitual daytime napping and cognition and brain structure. METHODS: Data were from UK Biobank (maximum n = 378,932 and mean age = 57 years). Our exposure (daytime napping) was instrumented using 92 previously identified genome-wide, independent genetic variants (single-nucleotide polymorphisms, SNPs). Our outcomes were total brain volume, hippocampal volume, reaction time, and visual memory. Inverse-variance weighted was implemented, with sensitivity analyses (Mendelian randomization-Egger and Weighted Median Estimator) for horizontal pleiotropy. We tested different daytime napping instruments to ensure the robustness of our results. RESULTS: Using Mendelian randomization, we found an association between habitual daytime napping and larger total brain volume (unstandardized ß = 15.80 cm3 and 95% CI = 0.25; 31.34) but not hippocampal volume (ß = -0.03 cm3 and 95% CI = -0.13;0.06), reaction time (expß = 1.01 and 95% CI = 1.00;1.03), or visual memory (expß = 0.99 and 95% CI = 0.94;1.05). Additional analyses with 47 SNPs (adjusted for excessive daytime sleepiness), 86 SNPs (excluding sleep apnea), and 17 SNPs (no sample overlap with UK Biobank) were largely consistent with our main findings. No evidence of horizontal pleiotropy was found. CONCLUSIONS: Our findings suggest a modest causal association between habitual daytime napping and larger total brain volume. Future studies could focus on the associations between napping and other cognitive or brain outcomes and replication of these findings using other datasets and methods.

Event-related potentials during the ultimatum game in people with symptoms of depression and/or social anxiety.

Depression and social anxiety are common disorders that have a profound impact on social functioning. The need for studying the neural substrates of social interactions in mental disorders using interactive tasks has been emphasized. The field of neuroeconomics, which combines neuroscience techniques and behavioral economics multiplayer tasks such as the Ultimatum Game (UG), can contribute in this direction. We assessed emotions, behavior, and Event-Related Potentials in participants with depression and/or social anxiety symptoms (MD/SA, n = 63, 57 females) and healthy controls (n = 72, 67 females), while they played the UG. In this task, participants received fair, mid-value, and unfair offers from other players. Mixed linear models were implemented to assess trial level changes in neural activity. The MD/SA group reported higher levels of sadness in response to mid-value and unfair offers compared to controls. In controls, the Medial Frontal Negativity associated with fair offers increased over time, while this dynamic was not observed in the MD/SA group. The MD/SA group showed a decreased P3/LPP in all offers, compared to controls. These results indicate an enhanced negative emotional response to unfairness in the MD/SA group. Neural results reveal a blunted response over time to positive social stimuli in the MD/SA group. Moreover, between-group differences in P3/LPP may relate to a reduced saliency of offers and/or to a reduced availability of resources for processing incoming stimuli in the MD/SA group. Findings may shed light into the neural substrates of social difficulties in these disorders.

Longitudinal changes in depression and anxiety during COVID-19 crisis in Uruguay.

Longitudinal studies have reported decreased mental health symptoms throughout the COVID-19 crisis, while others have found improvements or no changes across time. However, most research was carried out in developed countries, with a high incidence of COVID-19 and, in several cases, mandatory lockdowns. Considering that Uruguay (a developing country) had a low COVID-19 incidence at the moment of this study and has implemented a mild lockdown, we aimed to evaluate the effect of time and mobility (using Google mobility data) on symptoms of anxiety and depression. A longitudinal panel study with six repeated measures was carried out to evaluate depressive (BDI-II) and anxiety (STAI-S) symptoms during the pandemic. A decline in symptoms of anxiety and depression was found across time. Interestingly, this effect was modulated by age; a greater difference in the symptomatology between age groups was found at the beginning of the measurements than at the end, with the youngest reporting the most severe symptoms. Finally, we found that depressive symptoms decreased as mobility increased. Overall, our findings indicate an improvement in mental health as quarantine passed and mobility increased but following a different pattern depending on age. Monitoring these trajectories is imperative moving forward, especially in vulnerable groups. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-022-03460-w.

Neural processing of iterated prisoner's dilemma outcomes indicates next-round choice and speed to reciprocate cooperation.

The iterated prisoner's dilemma (iPD) game is a well-established model for testing how people cooperate, and the neural processes that unfold after its distinct outcomes have been partly described. Recent theoretical models suggest evolution favors intuitive cooperation, which raises questions on the behavioral but also neural timelines involved. We studied the outcome/feedback stage of iPD rounds with electroencephalography (EEG) methods. Results showed that neural signals associated with this stage also relate to future choice, in an outcome-dependent manner: (i) after zero-gain "sucker's payoffs" (unreciprocated cooperation), a participant's decision thereafter relates to changes to the feedback-related negativity (FRN); (ii) after one-sided non-cooperation (participant wins at co-player's expense), by the P3; (iii) after mutual cooperation, by late frontal delta-band modulations. Critically, faster reciprocation behavior towards a co-player's choice to cooperate was predicted, on a single-trial basis, by players' P3 and frontal delta modulations at the immediately preceding trial. Delta-band signaling is discussed in relation to homeostatic regulation processing in the literature. The findings relate the early outcome/feedback stage to subsequent decisional processes in the iPD, providing a first neural account of the brief timelines implied in heuristic modes of cooperation.

Social avoidance in depression: A study using a social decision-making task.

Depression significantly affects interpersonal functioning. Social avoidance may play an important role in depression, limiting opportunities and social skills acquisition, contributing to the maintenance of social difficulties. In the last few years, the need for studying social interactions using interactive tasks has been highlighted. This study investigated social avoidance in unmedicated depressed (n = 26) and matched healthy control (n = 26) participants, using a novel computerized social decision-making task (the TEAM task). In this task, participants choose between a social option (playing in a team with a coplayer) and an individual option (playing alone). Although the social option is more profitable from a material point of view, it can also be challenging because of social comparison and guilt feelings for failing the team. It was found that the higher the rank of the coplayer, the stronger the negative emotions (shame, guilt) reported by participants and the more they opted for the individual option. Depressed participants reported significantly less positive (happiness) and more negative (shame, guilt, disappointment) feelings regarding the task. Importantly, depressed participants chose the individual option significantly more often than controls, which led to lower gains in this group. Furthermore, as the task progressed, controls selected the individual option less often, whereas depressed participants selected the individual option more often. Our findings illustrate the importance of social avoidance in depression and how this behavior can lead to negative consequences. They also highlight the role of social comparison and guilt-related processes in underlying social avoidance in depression. (PsycINFO Database Record (c) 2019 APA, all rights reserved).