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Introduction Recent genome-wide association studies (GWAS) of individual sleep traits have identified hundreds of genetic loci, often implicating genes and biological pathways that are shared across sleep phenotypes. Modeling multiple dimensions of sleep may allow identification of common underlying genetic mechanisms and complement analyses of individual traits. Moreover, construction of novel sleep health scores, accounting for correlations between traits, has the potential to enhance specificity and power for genetic analyses. Methods We performed GWAS of composite sleep scores derived from five sleep questions characterizing 413,904 individuals of European ancestry from the UK Biobank. We constructed an additive sleep score (SS-add) as a sum of up to five favorable self-reported sleep behaviors (sleep duration of 7-8 hours, early chronotype, few insomnia symptoms, no snoring, and no excessive daytime sleepiness) as well as five principal component scores (SS-PC1 – SS-PC5) using the underlying sleep traits. SNP-level association studies of the sleep scores were complemented with multiple follow-up analyses, including investigation of pathway, tissue, and cell-type enrichments, as well as comprehensive genetic correlation (381 representative phenotypes) and bi-directional Mendelian randomization (MR) analyses (40 selected phenotypes). Results Sleep scores SS-PC1 (interpretable as longer duration sleep without insomnia symptoms) and SS-PC2 (healthy sleep without snoring or sleepiness) showed higher heritability (respectively 11.7% and 9.3%) compared with their primary underlying traits. SS-PC3 (loading strongly on chronotype) showed highest overall heritability (15.3%). Accounting for the six GWAS, we identified 28 significant novel loci (p< 8.3e-9), 31 additional novel loci (p< 5e-8), and 341 loci previously reported (p< 5e-8) by GWAS of individual sleep traits. Associated loci mapped to genes enriched in expression in brain tissues, and in metabolic and neuronal pathways. Numerous neurological, cardiometabolic and other traits were genetically correlated with sleep health (104 with|rho_g|>0.3, p< 2e-5). MR associations (p< 2e-4) pointed to causes (BMI [SS-PC2/PC4], smoking [SS-add/PC1], lower socio-economic status [SS-add/PC5]) and consequences (coronary heart disease [SS-add/PC1], pain [SS-PC1/5]) of poor sleep. Conclusion Composite sleep health scores revealed novel genetic mechanisms of related sleep behaviors, helped clarify relationships with neurological and cardiometabolic traits, and deserve further investigation. Support (if any) R01HL153814 (to H.W.), NHLBI R35HL135818 (to S.R.), 1R01HL146751 (to R.S.), UKB Application 6818.

Introduction Circadian rhythm disturbance is a common feature of many psychiatric disorders. Light is the primary input to the circadian clock, with daytime light strengthening rhythms and night light disrupting them. Therefore, habitual light exposure may represent an environmental risk factor for susceptibility to psychiatric disorders. Methods We performed the largest to-date cross-sectional analysis of light, sleep, physical activity, and mental health in participants from the UK Biobank actigraphy cohort (n = 86,772 adults; aged 62.4 ± 7.4 years; 57% women). We examined the independent association of day and night light exposure intensity with covariate-adjusted risk for psychiatric disorders and self-harm. Results Greater night light exposure was associated with increased risk for major depressive disorder, generalized anxiety disorder, PTSD, psychosis, bipolar disorder, and self-harm. Independent of night light, greater day light exposure was associated with reduced risk for major depressive disorder, PTSD, psychosis, and self-harm. These findings were robust to adjustment for sociodemographics, photoperiod, physical activity, and sleep quality. Conclusion Our findings demonstrate that low day light and bright night light exposure are associated with a wide range of psychiatric outcomes. Avoiding light at night and seeking light during the day may be a simple and effective, non-pharmacological means of broadly improving mental health. Support (if any)

Spouses may affect each other’s sleeping behaviour. In 47,420 spouse-pairs from the UK Biobank, we found a weak positive phenotypic correlation between spouses for self-reported sleep duration (r=0.11; 95% CI=0.10, 0.12) and a weak inverse correlation for chronotype (diurnal preference) (r=-0.11; -0.12, -0.10), which replicated in up to 127,035 23andMe spouse-pairs. Using accelerometer data on 3,454 UK Biobank spouse-pairs, the correlation for derived sleep duration was similar to self-report (r=0.12; 0.09, 0.15). Timing of diurnal activity was positively correlated (r=0.24; 0.21, 0.27) in contrast to the inverse correlation for chronotype. In Mendelian randomization analysis, positive effects of sleep duration (mean difference=0.13; 0.04, 0.23 SD per SD) and diurnal activity (0.49; 0.03, 0.94) were observed, as were inverse effects of chronotype (−0.15; -0.26, -0.04) and snoring (−0.15; -0.27, -0.04). Findings support the notion that an individual’s sleep may impact that of their partner, with implications for sleep health.

Introduction Excessive daytime sleepiness (EDS) affects 10-20% of the population and is associated with cardiovascular diseases (CVD) and mortality. However, EDS is heterogeneous, associated with both short and long sleep duration. It is unclear whether each subtype is related to CVD. Methods To understand the association of EDS subtypes (stratified by sleep duration) with incident myocardial infarction (MI), we perform multivariable Cox proportional hazards regression on MI using longitudinal medical record data of 471,991 individuals free of CVD at baseline from the UK Biobank. Baseline EDS and sleep duration were assessed by self-reported questionnaires. Results After adjusting for multiple social-demographic and behavioral factors, EDS with long sleep (³9 hours) was associated with a 91% increased incidence of MI (HR=1.91, 95% CI 1.34-2.71) compared to healthy sleep pattern (sleeping 6-9 hours without sleepiness), while EDS with normal (6-9 hours) or short sleep (≤6 hours) was not associated with incident MI. Long sleep without sleepiness was associated with a 39% increase in incident MI (HR=1.39, 95% CI 1.14-1.71). The association of EDS with long sleep was not explained by chronotype, insomnia, sleep apnea, depression, hypertension, or type 2 diabetes, but was confounded with self-reported overall health conditions (HR=1.46, 95% CI 1.02-2.08 after adjustment). Conclusion Our study suggests the previous association evidence of EDS increasing risk of MI may be primarily driven by its long sleep subtype (high “sleep propensity”), but the underlying mechanisms are unclear. Future work is needed to understand whether there are targetable interventions for this novel sleep phenotype that may improve cardiovascular health. Support (If Any) This research has been conducted using the UK Biobank Resource under Application Number 6818. Funding supports: NHLBI R35HL135818 and R01HL153814.

BACKGROUND Digital diabetes management systems have the potential to deliver cost-effective self-management support. DiabetesMyWay (DMW) is a platform for an open access website that includes a variety of multimedia resources including offering patients access to their clinical data in the form of an electronic personal health record. DMW aims to improve both the outcomes and experience of people with T2D, and provide them with a single care record which can be shared with their clinicians to support consultations, clinical decision making, care planning and self-management advice. OBJECTIVE The objective of this study is to evaluate the effectiveness of DMW and to explore acceptability to patients and clinicians METHODS A consensus approach to recruitment will be taken; all adults registered with type 2 diabetes, registered with a GP in the study area will be eligible. We will take a mixed methods approach to data collection analysis. RESULTS The primary outcome for effectiveness will be HbA1c value post intervention in participants and controls receiving usual care; a qualitative exploration of acceptability and a cost effectiveness evaluation. CONCLUSIONS Digital interventions have potential to transform self-management of T2D and deliver major clinical, psychological and economic benefits. This test bed project aims to assess the impact of a range of digital interventions delivered through DiabetesMyWay in an ethnically and socially diverse group of people with type two diabetes in Greater Manchester.

Background The extent of coronary disease affects clinical outcomes and may predict the effectiveness of coronary revascularization with either coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score quantifies the extent of coronary disease. Objectives This study sought to determine whether SYNTAX scores predicted outcomes and the effectiveness of coronary revascularization compared with medical therapy in the BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. Methods Baseline SYNTAX scores were retrospectively calculated for BARI-2D patients without prior revascularization (N = 1,550) by angiographic laboratory investigators masked to patient characteristics and outcomes. The primary outcome was major cardiovascular events (a composite of death, myocardial infarction, and stroke) over 5 years. Results A mid/high SYNTAX score (≥23) was associated with a higher risk of major cardiovascular events (hazard ratio: 1.36, confidence interval: 1.07 to 1.75, p = 0.01). Patients in the CABG stratum had significantly higher SYNTAX scores: 36% had mid/high SYNTAX scores compared with 13% in the PCI stratum (p Conclusions Among patients with diabetes and stable ischemic heart disease, higher SYNTAX scores predict higher rates of major cardiovascular events and were associated with more favorable outcomes of revascularization compared with medical therapy among patients suitable for CABG. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes; NCT00006305)

The sonic hedgehog (Shh) signaling pathway is crucial for normal lung development. In the lung, epithelial-produced Shh signals via mesenchymal Gli1-3 transcription factors. Gli-null lung phenotypes suggest that Gli2 is the primary Gli transcription factor transducing Shh-regulated lung growth, although the mechanism has yet to be elucidated. To clarify the role of Gli2 during lung development, we overexpressed gli2 in the lung mesenchyme of mice, to investigate for changes in Shh signaling, and cellular proliferation. The ectopic overexpression of gli2 resulted in increased Shh pathway activation as evident by increased expression of shh, ptc1, ptc2, smo, hhip, and gli1. Interestingly, we also observed increased expression of gli3 transcripts. Using two different mouse models, gli3-null and gli3Delta699 (Gli3 constitutive repressor), it was found that Gli3 activity does not affect the levels of gli2 in the developing lung. Real-time PCR and immunoblotting revealed that there is increased expression of cyclins D1, D2, and E1 associated with increased gli2 levels. Furthermore, the increase and decrease of cyclins (associated with changes in gli2 levels) positively correlated with cellular proliferation, as assessed by phospho-histone H3 immunohistochemistry. To determine if Gli3 has an effect on cyclin expression in the developing lung, we measured the levels of cyclin D1, D2, and E1, in gli3-null and gli3Delta699 mice and compared them to their wild-type counterparts. However, no change in the levels of cyclins D1, D2, or E1 due to altered Gli3 was observed. These findings suggest that Gli2 and not Gli3 is the primary mediator of Shh signaling influencing fetal lung growth through cyclin regulation.

Lung development takes place in a relatively low-oxygen environment, which is beneficial for lung organogenesis, including vascular development. Hypoxia-inducible factor (HIF)-1 plays an important role in mediating oxygen-regulated events. HIF-1 is stable and initiates gene transcription under hypoxia, whereas in normoxia, interaction with the von Hippel-Lindau (VHL) tumor suppressor protein leads to rapid degradation of the HIF-1alpha subunit. Interaction with VHL requires hydroxylation of HIF-1alpha proline residues by prolyl hydroxylases (PHDs). We investigated the expression of the various components regulating HIF-1alpha stability in first trimester (8-14 weeks) human lungs. Spatial expression was assessed by immunohistochemistry and temporal expression by quantitative PCR. Immunoreactivity for PHD1, PHD3, and seven in absentia homolog (SIAH)1 was noted in the pulmonary epithelium. PHD2 was not expressed in the airway epithelium, but in the lung parenchyma. HIF-1alpha and vascular endothelial growth factor (VEGF) immunoreactivity were primarily detected in the branching epithelium. HIF-2alpha and ARNT proteins localized to the developing epithelium as well as mesenchymal, most likely vascular, structures in the parenchyma. VEGF receptor 2 (VEGFR2) was found in the subepithelium as well as in vascular structures of the mesenchyme. All components of the VEC complex (VHL, NEDD8, and Cullin2) were found in the epithelium. Quantitative PCR analysis demonstrated that VEGF, VEGFR1, HIF-1alpha, HIF-2alpha, ARNT, PHD1, PHD2, PHD3, and SIAH1 gene expression was constant during early pulmonary organogenesis. Cumulatively, the data suggest that the lung develops in a low-oxygen environment that allows for proper vascular development through HIF-regulated pathways.

Aims/hypothesis We aimed to describe the shape of observed relationships between risk factor levels and clinically important outcomes in type 2 diabetes after adjusting for multiple confounders. Methods We used retrospective longitudinal data on 246,544 adults with type 2 diabetes from 600 practices in the Clinical Practice Research Datalink, 2006–2012. Proportional hazards regression models quantified the risks of mortality and microvascular or macrovascular events associated with four modifiable biological variables (HbA1c, systolic BP, diastolic BP and total cholesterol), while controlling for important patient and practice covariates. Results U-shaped relationships were observed between all-cause mortality and levels of the four biometric risk factors. Lowest risks were associated with HbA1c 7.25–7.75% (56–61 mmol/mol), total cholesterol 3.5–4.5 mmol/l, systolic BP 135–145 mmHg and diastolic BP 82.5–87.5 mmHg. Coronary and stroke mortality related to the four risk factors in a positive, curvilinear way, with the exception of systolic BP, which related to deaths in a U-shape. Macrovascular events showed a positive and curvilinear relationship with HbA1c but a U-shaped relationship with total cholesterol and systolic BP. Microvascular events related to the four risk factors in a curvilinear way: positive for HbA1c and systolic BP but negative for cholesterol and diastolic BP. Conclusions/interpretation We identified several relationships that support a call for major changes to clinical practice. Most importantly, our results support trial data indicating that normalisation of glucose and BP can lead to poorer outcomes. This makes a strong case for target ranges for these risk factors rather than target levels.

Murine lung development is a complex process regulated by many factors guiding a carefully orchestrated series of events leading to mature lung formation. Many developmental pathways have been implicated in governing proper lung formation. Most notably, the Shh/Gli pathway shown to be crucial to the development of numerous other organ systems, is an absolute requirement for correct lung formation. Many interactions between the Shh pathway and other fundamental lung signalling molecules such as fibroblast growth factor 10 (Fgf10) have presented themselves. While the specifics of these interactions have yet to be elucidated, the consequence of their actions is paramount in guiding lung development.

Low oxygen stimulates pulmonary vascular development and airway branching and involves hypoxia-inducible factor (HIF). HIF is stable and initiates expression of angiogenic factors under hypoxia, whereas normoxia triggers hydroxylation of the HIF-1α subunit by prolyl hydroxylases (PHDs) and subsequent degradation. Herein, we investigated whether chemical stabilization of HIF-1α under normoxic (20% O2) conditions would stimulate vascular growth and branching morphogenesis in early lung explants. Tie2-LacZ (endothelial LacZ marker) mice were used for visualization of the vasculature. Embryonic day 11.5 (E11.5) lung buds were dissected and cultured in 20% O2 in the absence or presence of cobalt chloride (CoCl2, a hypoxia mimetic), dimethyloxalylglycine (DMOG; a nonspecific inhibitor of PHDs), or desferrioxamine (DFO; an iron chelator). Vascularization was assessed by X-gal staining, and terminal buds were counted. The fine vascular network surrounding the developing lung buds seen in control explants disappeared in CoCl2- and DFO-treated explants. Also, epithelial branching was reduced in the explants treated with CoCl2 and DFO. In contrast, DMOG inhibited branching but stimulated vascularization. Both DFO and DMOG increased nuclear HIF-1α protein levels, whereas CoCl2 had no effect. Since HIF-1α induces VEGF expression, the effect of SU-5416, a potent VEGF receptor (VEGFR) blocker, on early lung development was also investigated. Inhibition of VEGFR2 signaling in explants maintained under hypoxic (2% O2) conditions completely abolished vascularization and slightly decreased epithelial branching. Taken together, the data suggest that DMOG stabilization of HIF-1α during early development leads to a hypervascular lung and that airway branching proceeds without the vasculature, albeit at a slower rate.