Chronotype Genetic Variant in PER2 is Associated with Intrinsic Circadian Period in Humans

This is the final version. Available on open access from Nature Research via the DOI in this recordData Availability: The data that support the findings of this study from the UK BioBank will be made available at https://sleepgenetics.org and the underlying genotype and phenotype data are available through application to the UK Biobank. Other phenotype data are available on request, due to privacy or other restrictions, through co-corresponding author Dr. Scheer ([email protected]).The PERIOD2 (PER2) gene is a core molecular component of the circadian clock and plays an important role in the generation and maintenance of daily rhythms. rs35333999, a missense variant of PER2 common in European populations, has been shown to associate with later chronotype. Chronotype relates to the timing of biological and behavioral activities, including when we sleep, eat, and exercise, and later chronotype is associated with longer intrinsic circadian period (cycle length), a fundamental property of the circadian system. Thus, we tested whether this PER2 variant was associated with circadian period and found significant associations with longer intrinsic circadian period as measured under forced desynchrony protocols, the ‘gold standard’ for intrinsic circadian period assessment. Minor allele (T) carriers exhibited significantly longer circadian periods when determinations were based on either core body temperature or plasma melatonin measurements, as compared to non-carriers (by 12 and 11 min, respectively; accounting for ~7% of inter-individual variance). These findings provide a possible underlying biological mechanism for inter-individual differences in chronotype, and support the central role of PER2 in the human circadian timing system.European CommissionWellcome TrustMedical Research Council (MRC

Social jetlag, obesity and metabolic disorder: Investigation in a cohort study.

Background: Obesity is one of the leading causes of preventable death worldwide. Circadian rhythms are known to control both sleep timing and energy homeostasis, and disruptions in circadian rhythms have been linked with metabolic dysfunction and obesity-associated disease. In previous research, social jetlag, a measure of chronic circadian disruption caused by the discrepancy between our internal versus social clocks, was associated with elevated self-reported body mass index, possibly indicative of a more generalized association with obesity and metabolic dysfunction. Methods: We studied participants from the population-representative Dunedin Longitudinal Study (N=1037) to determine whether social jetlag was associated with clinically assessed measurements of metabolic phenotypes and disease indicators for obesity-related disease, specifically, indicators of inflammation and diabetes. Results: Our analysis was restricted to N=815 non-shift workers in our cohort. Among these participants, we found that social jetlag was associated with numerous clinically assessed measures of metabolic dysfunction and obesity. We distinguished between obese individuals who were metabolically healthy versus unhealthy, and found higher social jetlag levels in metabolically unhealthy obese individuals. Among metabolically unhealthy obese individuals, social jetlag was additionally associated with elevated glycated hemoglobin and an indicator of inflammation. Conclusions: The findings are consistent with the possibility that ‘living against our internal clock’ may contribute to metabolic dysfunction and its consequences. Further research aimed at understanding that the physiology and social features of social jetlag may inform obesity prevention and have ramifications for policies and practices that contribute to increased social jetlag, such as work schedules and daylight savings time

Daily circadian misalignment impairs human cognitive performance task-dependently.

Shift work increases the risk for human errors, such that drowsiness due to shift work has contributed to major industrial disasters, including Space Shuttle Challenger, Chernobyl and Alaska Oil Spill disasters, with extraordinary socio-economical costs. Overnight operations pose a challenge because our circadian biology inhibits cognitive performance at night. Yet how the circadian system modulates cognition over multiple days under realistic shift work conditions remains to be established. Importantly, because task-specific cognitive brain regions show different 24-h circadian dynamics, we hypothesize that circadian misalignment impacts cognition task-dependently. Using a biologically-driven paradigm mimicking night shift work, with a randomized, cross-over design, we show that misalignment between the circadian pacemaker and behavioral/environmental cycles increases cognitive vulnerability on sustained attention, cognitive throughput, information processing and visual-motor performance over multiple days, compared to circadian alignment (day shifts). Circadian misalignment effects are task-dependent: while they acutely impair sustained attention with recovery after 3-days, they progressively hinder daily learning. Individuals felt sleepier during circadian misalignment, but they did not rate their performance as worse. Furthermore, circadian misalignment effects on sustained attention depended on prior sleep history. Collectively, daily circadian misalignment may provide an important biological framework for developing countermeasures against adverse cognitive effects in shift workers

Effects of circadian misalignment on cognition in chronic shift workers.

Shift work is associated with increased human operational errors, presumably due to the circadian timing system that inhibits optimal cognitive function during the night. Circadian misalignment, which is the misalignment between the circadian pacemaker and behavioral/environmental cycles, impairs cognitive performance in non-shift workers. However, it remains uncertain whether the adverse cognitive consequences of circadian misalignment are also observed in chronic shift workers. Thus, we investigated the effects of circadian misalignment on cognitive performance in chronic shift workers. Using a randomized, cross-over design that simulated day shift work (circadian alignment) and night shift work (circadian misalignment), we show that circadian misalignment increases cognitive vulnerability on sustained attention, information processing and visual-motor performance, particularly after more than 10 hours of scheduled wakefulness. Furthermore, their increased levels of subjective sleepiness and their decreased sleep efficiency were significantly associated with impaired sustained attention and visual-motor performance. Our data suggest that circadian misalignment dramatically deteriorates cognitive performance in chronic shift workers under circadian misalignment. This increased cognitive vulnerability may have important safety consequences, given the increasing number of nighttime jobs that crucially rely on the availability of cognitive resources

Social jetlag and dietary intake: A systematic review

The objective of the current systematic review was to critically review the available evidence regarding the link between social jetlag and diet among the general population using observational studies. Electronic databases, including PubMed, Scopus, and ISI Web of Sciences were searched systematically. We reviewed 348 references, of which 17 studies met inclusion criteria with a total sample size of 28,905. Qualitative analysis indicated a negative association between social jetlag and adherence to healthy eating habits, including a negative associ-ation with empirically-derived healthy dietary patterns, Japanese dietary patterns, Baltic Sea dietary patterns, and the Mediterranean diet, as well as a positive association with Meat and Starchy dietary pattern. On the other hand, the findings on the link of social jetlag with food groups and nutrients were mixed and controversial, except for a more consistent increase in sugar-sweetened beverages, total fat, and saturated fat intake. Our results indicate a possible link between social jetlag and dietary intake. Research suggests that individuals experiencing greater social jetlag exhibit reduced adherence to a healthy eating pattern. However, it is important to note that the reported association lacks consensus, emphasizing the need for additional longitudinal studies to gain further insights into this matter.

Social jetlag and obesity: A systematic review and meta-analysis

Social jetlag, the weekly variation in sleep timing, is proposed to contribute to increased obesity risk, potentially because of the misalignment of behavioral cycles relative to the endogenous circadian timing system. This systematic review and meta-analysis aim to determine the association between social jetlag and adiposity-related measures using observational studies. We reviewed 477 references, of which 43 studies met inclusion criteria with a total sample size of 231,648. There was a positive association between social jetlag and body mass index (correlation coefficient r: 0.12; 95%CI, 0.07, 0.17; P < 0.001; I(2) = 94.99%), fat mass (r: 0.10; 95%CI, 0.05, 0.15; P < 0.001; I(2) = 0.00%), fat mass index (fat mass divided by height in meter squared, beta: 0.14 kg/m(2) ; 95%CI, 0.05, 0.23; P < 0.001; I(2) = 56.50%), percent of body fat (r: 0.37; 95%CI, 0.33, 0.41; P < 0.001; I(2) = 96.17%), waist circumference (r: 0.15; 95%CI, 0.06, 0.24; P = 0.001; I(2) = 90.83%), and the risk of having overweight/obesity (odds ratio: 1.20; 95%CI, 1.02, 1.140; P = 0.039; I(2) = 98.25%). Social jetlag is positively and consistently associated with multiple obesity-related anthropometric measures. Further studies are needed to test causality, underlying mechanisms, and whether obesity interventions based on increasing regularity of the sleep/wake cycle can aid in the battle against the obesity pandemic

Impact of mental stress, the circadian system and their interaction on human cardiovascular function.

The risk for adverse cardiovascular events (e.g., myocardial infarction, sudden cardiac death) peaks in the morning, possibly due to the effects of the endogenous circadian system on cardiovascular risk factors, or the occurrence in the morning of specific triggers, such as mental stress. To assess any interacting effects on cardiovascular function of mental stress and the circadian system, 12 healthy adults underwent a 240-h protocol with all measurements and behaviors scheduled evenly across the circadian cycle. Mental stress was repeatedly induced by performance-motivated serial addition tasks. Cardiovascular measures included hemodynamic function (heart rate, blood pressure), circulating catecholamines (epinephrine, norepinephrine), and estimates of sympathovagal balance and cardiac vagal modulation derived from heart rate variability analyses. Mental stress increased hemodynamic function, sympathovagal balance and epinephrine, and decreased cardiac vagal modulation. Endogenous circadian variation occurred in all cardiovascular measures: sympathovagal balance peaked in the circadian morning (∼9 AM), cardiac vagal modulation in the circadian night (∼4 AM), and heart rate and circulating catecholamines in the late circadian morning/early afternoon (∼12 PM). Importantly, the effects of mental stress and the endogenous circadian system on cardiovascular function occurred in conjunction, such that mental stress in the circadian morning caused greatest sympathovagal balance. This summation of effects could contribute to the increased morning cardiovascular vulnerability