Pathway-Specific Polygenic Risk Scores Identify Obstructive Sleep Apnea-Related Pathways Differentially Moderating Genetic Susceptibility to Coronary Artery Disease.

BACKGROUND: Obstructive sleep apnea (OSA) and its features, such as chronic intermittent hypoxia, may differentially affect specific molecular pathways and processes in the pathogenesis of coronary artery disease (CAD) and influence the subsequent risk and severity of CAD events. In particular, competing adverse (eg, inflammatory) and protective (eg, increased coronary collateral blood flow) mechanisms may operate, but remain poorly understood. We hypothesize that common genetic variation in selected molecular pathways influences the likelihood of CAD events differently in individuals with and without OSA, in a pathway-dependent manner. METHODS: We selected a cross-sectional sample of 471 877 participants from the UK Biobank, with 4974 ascertained to have OSA, 25 988 to have CAD, and 711 to have both. We calculated pathway-specific polygenic risk scores for CAD, based on 6.6 million common variants evaluated in the CARDIoGRAMplusC4D genome-wide association study (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics), annotated to specific genes and pathways using functional genomics databases. Based on prior evidence of involvement with intermittent hypoxia and CAD, we tested pathway-specific polygenic risk scores for the HIF1 (hypoxia-inducible factor 1), VEGF (vascular endothelial growth factor), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) and TNF (tumor necrosis factor) signaling pathways. RESULTS: In a multivariable-adjusted logistic generalized additive model, elevated pathway-specific polygenic risk scores for the Kyoto Encyclopedia of Genes and Genomes VEGF pathway (39 genes) associated with protection for CAD in OSA (interaction odds ratio 0.86, P=6×10-4). By contrast, the genome-wide CAD PRS did not show evidence of statistical interaction with OSA. CONCLUSIONS: We find evidence that pathway-specific genetic risk of CAD differs between individuals with and without OSA in a qualitatively pathway-dependent manner. These results provide evidence that gene-by-environment interaction influences CAD risk in certain pathways among people with OSA, an effect that is not well-captured by the genome-wide PRS. This invites further study of how OSA interacts with genetic risk at the molecular level and suggests eventual personalization of OSA treatment to reduce CAD risk according to individual pathway-specific genetic risk profiles.

Interaction of obesity polygenic score with lifestyle risk factors in an electronic health record biobank.

BACKGROUND: Genetic and lifestyle factors have considerable effects on obesity and related diseases, yet their effects in a clinical cohort are unknown. This study in a patient biobank examined associations of a BMI polygenic risk score (PRS), and its interactions with lifestyle risk factors, with clinically measured BMI and clinical phenotypes. METHODS: The Mass General Brigham (MGB) Biobank is a hospital-based cohort with electronic health record, genetic, and lifestyle data. A PRS for obesity was generated using 97 genetic variants for BMI. An obesity lifestyle risk index using survey responses to obesogenic lifestyle risk factors (alcohol, education, exercise, sleep, smoking, and shift work) was used to dichotomize the cohort into high and low obesogenic index based on the population median. Height and weight were measured at a clinical visit. Multivariable linear cross-sectional associations of the PRS with BMI and interactions with the obesity lifestyle risk index were conducted. In phenome-wide association analyses (PheWAS), similar logistic models were conducted for 675 disease outcomes derived from billing codes. RESULTS: Thirty-three thousand five hundred eleven patients were analyzed (53.1% female; age 60.0 years; BMI 28.3 kg/m2), of which 17,040 completed the lifestyle survey (57.5% female; age: 60.2; BMI: 28.1 (6.2) kg/m2). Each standard deviation increment in the PRS was associated with 0.83 kg/m2 unit increase in BMI (95% confidence interval (CI) =0.76, 0.90). There was an interaction between the obesity PRS and obesity lifestyle risk index on BMI. The difference in BMI between those with a high and low obesogenic index was 3.18 kg/m2 in patients in the highest decile of PRS, whereas that difference was only 1.55 kg/m2 in patients in the lowest decile of PRS. In PheWAS, the obesity PRS was associated with 40 diseases spanning endocrine/metabolic, circulatory, and 8 other disease groups. No interactions were evident between the PRS and the index on disease outcomes. CONCLUSIONS: In this hospital-based clinical biobank, obesity risk conferred by common genetic variants was associated with elevated BMI and this risk was attenuated by a healthier patient lifestyle. Continued consideration of the role of lifestyle in the context of genetic predisposition in healthcare settings is necessary to quantify the extent to which modifiable lifestyle risk factors may moderate genetic predisposition and inform clinical action to achieve personalized medicine.

Sleep and circadian rhythms: pillars of health-a Keystone Symposia report.

The human circadian system consists of the master clock in the suprachiasmatic nuclei of the hypothalamus as well as in peripheral molecular clocks located in organs throughout the body. This system plays a major role in the temporal organization of biological and physiological processes, such as body temperature, blood pressure, hormone secretion, gene expression, and immune functions, which all manifest consistent diurnal patterns. Many facets of modern life, such as work schedules, travel, and social activities, can lead to sleep/wake and eating schedules that are misaligned relative to the biological clock. This misalignment can disrupt and impair physiological and psychological parameters that may ultimately put people at higher risk for chronic diseases like cancer, cardiovascular disease, and other metabolic disorders. Understanding the mechanisms that regulate sleep circadian rhythms may ultimately lead to insights on behavioral interventions that can lower the risk of these diseases. On February 25, 2021, experts in sleep, circadian rhythms, and chronobiology met virtually for the Keystone eSymposium "Sleep & Circadian Rhythms: Pillars of Health" to discuss the latest research for understanding the bidirectional relationships between sleep, circadian rhythms, and health and disease.

Habitual Sleep Duration, Daytime Napping, and Dietary Intake: A Mendelian Randomization Study.

BACKGROUND: Chronic inadequate sleep and frequent daytime napping may inflict deleterious health effects including weight gain, cardiometabolic and psychiatric diseases, and cancer. It is plausible that these relations may be partly influenced by the consumption of suboptimal diets. OBJECTIVES: The study aimed to identify potential causal links of genetically proxied longer habitual sleep duration and more frequent daytime napping on 61 dietary variables derived from an FFQ. In addition, the study aimed to assess potential bidirectional causal links between habitual sleep duration or daytime napping and macronutrient composition. METHODS: Genetic variants robustly associated with habitual sleep duration and daytime napping from published genome-wide association analyses were used. Outcomes included 61 dietary variables estimated from FFQs in the UK Biobank (n = 361,194). For bidirectional associations with macronutrient composition, genetic variants associated with percentage of energy from carbohydrate, fat, and protein were used. Two-sample Mendelian randomization (MR) effects were estimated with inverse-variance weighted (IVW) analysis. RESULTS: In 2-sample MR, genetically proxied longer sleep duration was associated with a 0.068 (95% CI: 0.034, 0.103) category increase in salad/raw vegetable intake [P false discovery rate (FDR) = 0.006] per hour of sleep and with "no major dietary changes in the past 5 years" (P FDR = 0.043). No associations were evident for daytime napping on dietary variables (all P FDR > 0.05). In addition, there were no bidirectional associations between habitual sleep duration or daytime napping with the relative intake of carbohydrate, fat, and protein (all P IVW > 0.05). CONCLUSIONS: In this MR study, there was modest evidence for associations between habitual sleep duration with dietary intake and no evidence for associations between daytime napping frequency with dietary intake. These preliminary findings suggest that changes to habitual sleep duration or daytime napping frequency may have limited impact on long-term changes in dietary intake.

Selection into shift work is influenced by educational attainment and body mass index: a Mendelian randomization study in the UK Biobank.

BACKGROUND: Shift work is associated with increased cardiometabolic disease risk. This observation may be partly explained by cardiometabolic risk factors having a role in the selection of individuals into or out of shift work. We performed Mendelian randomization (MR) analyses in the UK Biobank (UKB) to test this hypothesis. METHODS: We used genetic risk scores (GRS) to proxy nine cardiometabolic risk factors and diseases (including educational attainment, body mass index (BMI), smoking, and alcohol consumption), and tested associations of each GRS with self-reported frequency of current shift work among employed UKB participants of European ancestry (n = 190 573). We used summary-level MR sensitivity analyses to assess robustness of the identified effects, and we tested whether effects were mediated through sleep timing preference. RESULTS: Genetically instrumented liability to lower educational attainment (odds ratio (OR) per 3.6 fewer years in educational attainment = 2.40, 95% confidence interval (CI) = 2.22-2.59, P = 4.84 × 10-20) and higher body mass index (OR per 4.7 kg/m2 higher BMI = 1.30, 95% CI = 1.14-1.47, P = 5.85 × 10-5) increased odds of reporting participation in frequent shift work. Results were unchanged in sensitivity analyses allowing for different assumptions regarding horizontal pleiotropy. No selection effects were evident for the remaining exposures, nor for any exposures on selection out of shift work. Sleep timing preference did not mediate the effects of BMI and educational attainment on selection into shift work. CONCLUSIONS: Liability to lower educational attainment and higher BMI may influence selection into shift work. This phenomenon may bias epidemiological studies of shift work that are performed in the UKB.

Night shift work is associated with an increased risk of asthma.

INTRODUCTION: Shift work causes misalignment between internal circadian time and the external light/dark cycle and is associated with metabolic disorders and cancer. Approximately 20% of the working population in industrialised countries work permanent or rotating night shifts, exposing this large population to the risk of circadian misalignment-driven disease. Analysis of the impact of shift work on chronic inflammatory diseases is lacking. We investigated the association between shift work and asthma. METHODS: We describe the cross-sectional relationship between shift work and prevalent asthma in >280000 UK Biobank participants, making adjustments for major confounding factors (smoking history, ethnicity, socioeconomic status, physical activity, body mass index). We also investigated chronotype. RESULTS: Compared with day workers, 'permanent' night shift workers had a higher likelihood of moderate-severe asthma (OR 1.36 (95% CI 1.03 to 1.8)) and all asthma (OR 1.23 (95% CI 1.03 to 1.46)). Individuals doing any type of shift work had higher adjusted odds of wheeze/whistling in the chest. Shift workers who never or rarely worked on nights and people working permanent nights had a higher adjusted likelihood of having reduced lung function (FEV1 <80% predicted). We found an increase in the risk of moderate-severe asthma in morning chronotypes working irregular shifts, including nights (OR 1.55 (95% CI 1.06 to 2.27)). CONCLUSIONS: The public health implications of these findings are far-reaching due to the high prevalence and co-occurrence of both asthma and shift work. Future longitudinal follow-up studies are needed to determine if modifying shift work schedules to take into account chronotype might present a public health measure to reduce the risk of developing inflammatory diseases such as asthma.

Investigating causal relations between sleep traits and risk of breast cancer in women: mendelian randomisation study.

OBJECTIVE: To examine whether sleep traits have a causal effect on risk of breast cancer. DESIGN: Mendelian randomisation study. SETTING: UK Biobank prospective cohort study and Breast Cancer Association Consortium (BCAC) case-control genome-wide association study. PARTICIPANTS: 156 848 women in the multivariable regression and one sample mendelian randomisation (MR) analysis in UK Biobank (7784 with a breast cancer diagnosis) and 122 977 breast cancer cases and 105 974 controls from BCAC in the two sample MR analysis. EXPOSURES: Self reported chronotype (morning or evening preference), insomnia symptoms, and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits. MAIN OUTCOME MEASURE: Breast cancer diagnosis. RESULTS: In multivariable regression analysis using UK Biobank data on breast cancer incidence, morning preference was inversely associated with breast cancer (hazard ratio 0.95, 95% confidence interval 0.93 to 0.98 per category increase), whereas there was little evidence for an association between sleep duration and insomnia symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated with sleep duration, and 57 SNPs associated with insomnia symptoms, one sample MR analysis in UK Biobank provided some supportive evidence for a protective effect of morning preference on breast cancer risk (0.85, 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia symptoms. Two sample MR using data from BCAC supported findings for a protective effect of morning preference (inverse variance weighted odds ratio 0.88, 95% confidence interval 0.82 to 0.93 per category increase) and adverse effect of increased sleep duration (1.19, 1.02 to 1.39 per hour increase) on breast cancer risk (both oestrogen receptor positive and oestrogen receptor negative), whereas evidence for insomnia symptoms was inconsistent. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy. CONCLUSIONS: Findings showed consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of increased sleep duration on breast cancer risk.

Genome-wide association study of breakfast skipping links clock regulation with food timing.

BACKGROUND: Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits. OBJECTIVES: The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait. METHODS: We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963). RESULTS: In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095). CONCLUSIONS: Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.

Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms.

Being a morning person is a behavioural indicator of a person's underlying circadian rhythm. Using genome-wide data from 697,828 UK Biobank and 23andMe participants we increase the number of genetic loci associated with being a morning person from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we find that the chronotype loci associate with sleep timing: the mean sleep timing of the 5% of individuals carrying the most morningness alleles is 25 min earlier than the 5% carrying the fewest. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomisation, we show that being a morning person is causally associated with better mental health but does not affect BMI or risk of Type 2 diabetes. This study offers insights into circadian biology and its links to disease in humans.

Circulating Phylloquinone Concentrations and Risk of Type 2 Diabetes: A Mendelian Randomization Study.

This study investigated the causal relation between circulating phylloquinone (vitamin K1) concentrations and type 2 diabetes by using a Mendelian randomization (MR) approach. We used data from three studies: the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, Diabetes Genetics Replication and Meta-analysis (DIAGRAM), and the UK Biobank, resulting in 69,647 subjects with type 2 diabetes. We calculated a weighted genetic risk score including four genetic variants previously found to be associated with circulating phylloquinone concentrations. Inverse-variance weighted analysis was used to obtain a risk ratio (RR) for the causal relation between circulating phylloquinone concentrations and risk of type 2 diabetes. Presence of pleiotropy and the robustness of the results were assessed using MR-Egger and weighted-median analyses. Genetically predicted concentrations of circulating phylloquinone were associated with lower risk of type 2 diabetes with an RR of 0.93 (95% CI 0.89; 0.97) per every natural logarithm (Ln)-nmol/L-unit increase in circulating phylloquinone. The MR-Egger and weighted median analyses showed RRs of 0.94 (0.86; 1.02) and 0.93 (0.88; 0.98), respectively, indicating no pleiotropy. In conclusion, our study supports that higher circulating phylloquinone may be causally related with lower risk of type 2 diabetes, highlighting the importance of sufficient phylloquinone in the human diet.

PRKCZ methylation is associated with sunlight exposure in a North American but not a Mediterranean population.

Sunlight exposure has been shown to alter DNA methylation patterns across several human cell-types, including T-lymphocytes. Since epigenetic changes establish gene expression profiles, changes in DNA methylation induced by sunlight exposure warrant investigation. The purpose of this study was to assess the effects of sunlight exposure on CD4+ T-cell methylation patterns on an epigenome-wide scale in a North American population of European origin (n=991). In addition, we investigated the genetic contribution to epigenetic variation (methylQTL). We used linear regression to test the associations between methylation scores at 461,281 cytosine-phosphate-guanine (CpG) sites and sunlight exposure, followed by a genome-wide association analysis (methylQTL) to test for associations between methylation at the top CpG locus and common genetic variants, assuming an additive genetic model. We observed an epigenome-wide significant association between sunlight exposure and methylation status at cg26930596 (p=9.2×10(-8)), a CpG site located in protein kinase C zeta (PRKCZ), a gene previously shown to be entrained by light. MethylQTL analysis resulted in significant associations between cg26930596 and two intergenic single nucleotide polymorphisms on chromosome 3, rs4574216 (p=1.5×10(-10)) and rs4405858 (p=1.9×10(-9)). These common genetic variants reside downstream of WWTR1, a transcriptional co-activator of PRKCZ. Associations observed in the North American population, however, did not replicate in an independent Mediterranean cohort. Our preliminary results support the role of sunlight exposure in epigenetic processes, and lay the groundwork for future studies of the molecular link between sunlight and physiologic processes such as tumorigenesis and metabolism.