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.

Objectively regular sleep patterns and mortality in a prospective cohort: The Multi-Ethnic Study of Atherosclerosis.

Irregular sleep and non-optimal sleep duration separately have been shown to be associated with increased disease and mortality risk. We used data from the prospective cohort Multi-Ethnic Study of Atherosclerosis sleep study (2010-2013) to investigate: do aging adults whose sleep is objectively high in regularity in timing and duration, and of sufficient duration tend to have increased survival compared with those whose sleep is lower in regularity and duration, in a diverse US sample? At baseline, sleep was measured by 7-day wrist actigraphy, concurrent with at-home polysomnography and questionnaires. Objective metrics of sleep regularity and duration from actigraphy were used for statistical clustering using sparse k-means clustering. Two sleep patterns were identified: "regular-optimal" (average duration: 7.0 ± 1.0 hr obtained regularly) and "irregular-insufficient" (duration: 5.8 ± 1.4 hr obtained with twice the irregularity). Using proportional hazard models with multivariate adjustment, we estimated all-cause mortality hazard ratios. Among 1759 participants followed for a median of 7.0 years (Q1-Q3, 6.4-7.4 years), 176 deaths were recorded. The "regular-optimal" group had a 39% lower mortality hazard than did the "irregular-insufficient" sleep group (hazard ratio [95% confidence interval]: 0.61 [0.45, 0.83]) after adjusting for socio-demographics, lifestyle, medical comorbidities and sleep disorders. In conclusion, a "regular-optimal" sleep pattern was significantly associated with a lower hazard of all-cause mortality. The regular-optimal phenotype maps behaviourally to regular bed and wake times, suggesting sleep benefits of adherence to recommended healthy sleep practices, with further potential benefits for longevity.

Causal Association Between Subtypes of Excessive Daytime Sleepiness and Risk of Cardiovascular Diseases.

BACKGROUND: Excessive daytime sleepiness (EDS), experienced in 10% to 20% of the population, has been associated with cardiovascular disease and death. However, the condition is heterogeneous and is prevalent in individuals having short and long sleep duration. We sought to clarify the relationship between sleep duration subtypes of EDS with cardiovascular outcomes, accounting for these subtypes. METHODS AND RESULTS: We defined 3 sleep duration subtypes of excessive daytime sleepiness: normal (6-9 hours), short (<6 hours), and long (>9 hours), and compared these with a nonsleepy, normal-sleep-duration reference group. We analyzed their associations with incident myocardial infarction (MI) and stroke using medical records of 355 901 UK Biobank participants and performed 2-sample Mendelian randomization for each outcome. Compared with healthy sleep, long-sleep EDS was associated with an 83% increased rate of MI (hazard ratio, 1.83 [95% CI, 1.21-2.77]) during 8.2-year median follow-up, adjusting for multiple health and sociodemographic factors. Mendelian randomization analysis provided supporting evidence of a causal role for a genetic long-sleep EDS subtype in MI (inverse-variance weighted ß=1.995, P=0.001). In contrast, we did not find evidence that other subtypes of EDS were associated with incident MI or any associations with stroke (P>0.05). CONCLUSIONS: Our study suggests the previous evidence linking EDS with increased cardiovascular disease risk may be primarily driven by the effect of its long-sleep subtype on higher risk of MI. Underlying mechanisms remain to be investigated but may involve sleep irregularity and circadian disruption, suggesting a need for novel interventions in this population.

A polygenic risk score for Alzheimer's disease constructed using APOE-region variants has stronger association than APOE alleles with mild cognitive impairment in Hispanic/Latino adults in the U.S.

INTRODUCTION: Polygenic Risk Scores (PRSs) are summaries of genetic risk alleles for an outcome. METHODS: We used summary statistics from five GWASs of AD to construct PRSs in 4,189 diverse Hispanics/Latinos (mean age 63 years) from the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA). We assessed the PRS associations with MCI in the combined set of people and in diverse subgroups, and when including and excluding the APOE gene region. We also assessed PRS associations with MCI in an independent dataset from the Mass General Brigham Biobank. RESULTS: A simple sum of 5 PRSs ("PRSsum"), each constructed based on a different AD GWAS, was associated with MCI (OR = 1.28, 95% CI [1.14, 1.41]) in a model adjusted for counts of the APOE-[Formula: see text] and APOE-[Formula: see text] alleles. Associations of single-GWAS PRSs were weaker. When removing SNPs from the APOE region from the PRSs, the association of PRSsum with MCI was weaker (OR = 1.17, 95% CI [1.04,1.31] with adjustment for APOE alleles). In all association analyses, APOE-[Formula: see text] and APOE-[Formula: see text] alleles were not associated with MCI. DISCUSSION: A sum of AD PRSs is associated with MCI in Hispanic/Latino older adults. Despite no association of APOE-[Formula: see text] and APOE-[Formula: see text] alleles with MCI, the association of the AD PRS with MCI is stronger when including the APOE region. Thus, APOE variants different than the classic APOE alleles may be important predictors of MCI in Hispanic/Latino adults.

Associations between sleep health and grey matter volume in the UK Biobank cohort (n = 33 356).

As suggested by previous research, sleep health is assumed to be a key determinant of future morbidity and mortality. In line with this, recent studies have found that poor sleep is associated with impaired cognitive function. However, to date, little is known about brain structural abnormalities underlying this association. Although recent findings link sleep health deficits to specific alterations in grey matter volume, evidence remains inconsistent and reliant on small sample sizes. Addressing this problem, the current preregistered study investigated associations between sleep health and grey matter volume (139 imaging-derived phenotypes) in the UK Biobank cohort (33 356 participants). Drawing on a large sample size and consistent data acquisition, sleep duration, insomnia symptoms, daytime sleepiness, chronotype, sleep medication and sleep apnoea were examined. Our main analyses revealed that long sleep duration was systematically associated with larger grey matter volume of basal ganglia substructures. Insomnia symptoms, sleep medication and sleep apnoea were not associated with any of the 139 imaging-derived phenotypes. Short sleep duration, daytime sleepiness as well as late and early chronotype were associated with solitary imaging-derived phenotypes (no recognizable pattern, small effect sizes). To our knowledge, this is the largest study to test associations between sleep health and grey matter volume. Clinical implications of the association between long sleep duration and larger grey matter volume of basal ganglia are discussed. Insomnia symptoms as operationalized in the UK Biobank do not translate into grey matter volume findings.

Multi-dimensional sleep and mortality: The Multi-Ethnic Study of Atherosclerosis.

STUDY OBJECTIVES: Multiple sleep characteristics are informative of health, sleep characteristics cluster, and sleep health can be described as a composite of positive sleep attributes. We assessed the association between a sleep score reflecting multiple sleep dimensions, and mortality. We tested the hypothesis that more favorable sleep (higher sleep scores) is associated with lower mortality. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a racially and ethnically-diverse multi-site, prospective cohort study of US adults. Sleep was measured using unattended polysomnography, 7-day wrist actigraphy, and validated questionnaires (2010-2013). 1726 participants were followed for a median of 6.9 years (Q1-Q3, 6.4-7.4 years) until death (171 deaths) or last contact. Survival models were used to estimate the association between the exposure of sleep scores and the outcome of all-cause mortality, adjusting for socio-demographics, lifestyle, and medical comorbidities; follow-up analyses examined associations between individual metrics and mortality. The exposure, a sleep score, was constructed by an empirically-based Principal Components Analysis on 13 sleep metrics, selected a priori. RESULTS: After adjusting for multiple confounders, a 1 standard deviation (sd) higher sleep score was associated with 25% lower hazard of mortality (Hazard Ratio [HR]: 0.75; 95% Confidence interval: [0.65, 0.87]). The largest drivers of this association were: night-to-night sleep regularity, total sleep time, and the Apnea-Hypopnea Index. CONCLUSION: More favorable sleep across multiple characteristics, operationalized by a sleep score, is associated with lower risk of death in a diverse US cohort of adults. Results suggest that interventions that address multiple dimensions may provide novel approaches for improving health.

Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups.

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.

Correlations between complex human phenotypes vary by genetic background, gender, and environment.

We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet ∼20× faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we introduce "fractional genetic correlation" as the fraction of phenotypic correlation explained by genetics. Finally, we quantify the enrichment of correlations between phenotypic domains, each of which is comprised of multiple phenotypes. Altogether, we demonstrate that the observed correlations between complex human phenotypes depend on the genetic background of the individuals, their gender, and their environment.

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.

A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood.

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.

Corrigendum: Yoga, Meditation and Mind-Body Health: Increased BDNF, Cortisol Awakening Response, and Altered Inflammatory Marker Expression After a 3-Month Yoga and Meditation Retreat.

[This corrects the article DOI: 10.3389/fnhum.2017.00315.].

Range selective digital holographic imaging using FMCW lidar.

The integration of chirped frequency modulated continuous wave (FMCW) lidar techniques into digital holography enables range selective holographic imaging well beyond the depth of field of the system. The technique uses FMCW transmit and reference beams. By frequency shifting the reference beam to compensate for the typical FMCW beat frequency associated with a particular range, temporally stable holograms are formed for objects at the selected range. The holograms associated with objects at all other ranges oscillate and integrate towards zero. Experimental demonstrations of the technique are presented, showing enhanced imaging of objects at different ranges and cancellation of obscuring objects. The technique is expandable to range-Doppler selective digital holographic imaging.

Upregulated heme biosynthesis increases obstructive sleep apnea severity: a pathway-based Mendelian randomization study.

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Iron and heme metabolism, implicated in ventilatory control and OSA comorbidities, was associated with OSA phenotypes in recent admixture mapping and gene enrichment analyses. However, its causal contribution was unclear. In this study, we performed pathway-level transcriptional Mendelian randomization (MR) analysis to investigate the causal relationships between iron and heme related pathways and OSA. In primary analysis, we examined the expression level of four iron/heme Reactome pathways as exposures and four OSA traits as outcomes using cross-tissue cis-eQTLs from the Genotype-Tissue Expression portal and published genome-wide summary statistics of OSA. We identify a significant putative causal association between up-regulated heme biosynthesis pathway with higher sleep time percentage of hypoxemia (p = 6.14 × 10-3). This association is supported by consistency of point estimates in one-sample MR in the Multi-Ethnic Study of Atherosclerosis using high coverage DNA and RNA sequencing data generated by the Trans-Omics for Precision Medicine project. Secondary analysis for 37 additional iron/heme Gene Ontology pathways did not reveal any significant causal associations. This study suggests a causal association between increased heme biosynthesis and OSA severity.

Multidimensional sleep health in a diverse, aging adult cohort: Concepts, advances, and implications for research and intervention.

PURPOSE: To illustrate 2 frameshifts of multidimensional sleep health: i) use of composite sleep metrics; and ii) the correlations among sleep dimensions. PARTICIPANTS: 735 adults of diverse backgrounds aged <65 years who participated in the Multi-Ethnic Study of Atherosclerosis. MEASURES: In-home polysomnography, 7-day wrist actigraphy, and validated questionnaires. METHODS: The Buysse Ru SATED model-sleep regularity, satisfaction, alertness, timing, efficiency, duration-was operationalized, then extended by including additional measures of sleep architecture and sleep apnea from polysomnography and difficulties initiating sleep from questionnaire and sleep onset latency and duration [ir]regularity from actigraphy. We dichotomized sleep variables, operationalizing optimal and nonoptimal ranges as 1 and 0, respectively, summed into a sleep health score, and computed global sleep health scores via principal components analysis. FINDINGS: Participants showed low prevalence of sleep regularity in timing (<30 minutes standard deviation [SD]; 21.4% favorable) and duration (<60 minutes SD; 36.9%). Although 62.7% of participants demonstrated favorable sleep duration by actigraphy, few met criteria for favorable levels of % N3 (11.4%) or %R (34.1%). The average Sleep Health Score was 5.6 of 13 (higher is better). Sleep variables were variably intercorrelated (r = 0 to r = -0.72). The first principal component for each operationalization of sleep health was interpretable as a "health" score; all summary scores captured variable but systematic shifts towards more favorable sleep in each sleep variable. CONCLUSIONS: Multidimensional sleep health can be measured by complementary composite scores as well as consideration of multiple individual dimensions.

Digital holographic polarimeter using dual reference beam interferometry.

An off-axis digital holographic imaging polarimeter was developed to estimate the Jones matrices of an object. The Jones vector image of the electric field returned from the object is determined from a single holographic recording using the interference between the dual, nearly orthogonal, reference beams. The technique compensates for phase variations in the optical beam paths between the recorded holograms and relaxes the need to generate orthogonal illumination polarization states. A minimization algorithm was developed to compute an estimation of the Jones matrix image of an object based on a set of measured Jones vector images. A proof-of-concept demonstration was performed to compute an estimated Jones matrix image of a polarimetrically complex object using digital holograms recorded with 6 different illumination polarizations.

Racial-ethnic Differences in Actigraphy, Questionnaire, and Polysomnography Indicators of Healthy Sleep: The Multi-Ethnic Study of Atherosclerosis.

A paradigm shift in sleep science argues for a systematic, multidimensional approach to investigate sleep's association with disease and mortality and to address sleep disparities. We utilized the comprehensive sleep assessment of the Multi-Ethnic Study of Atherosclerosis (2010- 2013), a cohort of U.S. White, Black, Chinese, and Hispanic adults and older adults (n=1,736; mean age=68.3), to draw 13 sleep dimensions and create composite Sleep Health Scores to quantify multidimensional sleep health disparities. After age and sex adjustment in linear regression, compared to White participants, Black participants showed the greatest global sleep disparity, then Hispanic and Chinese participants. We estimated relative 'risk' of obtaining favorable sleep compared to White adults at the component level by race/ethnicity (lower is worse). The largest disparities were in objectively-measured sleep timing regularity (RRBlack [95% CI]: 0.37 [0.29,0.47], RRHispanic: 0.64 [0.52,0.78], RRChinese: 0.70 [0.54,0.90]) and duration regularity (RRBlack: 0.55 [0.47,0.65], RRHispanic: 0.76 [0.66,0.88], RRChinese: 0.74 [0.61,0.90]), after sex and age adjustment. Disparities in duration and continuity were also apparent, and Black adults were additionally disadvantaged in %N3 (slow wave sleep), sleepiness, and sleep timing (24-hour placement). Sleep timing regularity, duration regularity, duration, and continuity may comprise a multidimensional cluster of targets to reduce racial-ethnic sleep disparities.

Heritability of quantitative autism spectrum traits in adults: A family-based study.

Autism spectrum disorder (ASD) comprises a multi-dimensional set of quantitative behavioral traits expressed along a continuum in autistic and neurotypical individuals. ASD diagnosis-a dichotomous trait-is known to be highly heritable and has been used as the phenotype for most ASD genetic studies. But less is known about the heritability of autism spectrum quantitative traits, especially in adults, an important prerequisite for gene discovery. We sought to measure the heritability of many autism-relevant quantitative traits in adults high in autism spectrum traits and their extended family members. Among adults high in autism spectrum traits (n = 158) and their extended family members (n = 245), we calculated univariate and bivariate heritability estimates for 19 autism spectrum traits across several behavioral domains. We found nearly all tested autism spectrum quantitative traits to be significantly heritable (h2  = 0.24-0.79), including overall ASD traits, restricted repetitive behaviors, broader autism phenotype traits, social anxiety, and executive functioning. The degree of shared heritability varied based on method and specificity of the assessment measure. We found high shared heritability for the self-report measures and for most of the informant-report measures, with little shared heritability among performance-based cognition tasks. These findings suggest that many autism spectrum quantitative traits would be good, feasible candidates for future genetics studies, allowing for an increase in the power of autism gene discovery. Our findings suggest that the degree of shared heritability between traits depends on the assessment method (self-report vs. informant-report vs. performance-based tasks), as well as trait-specificity. LAY SUMMARY: We found that the scores from questionnaires and tasks measuring different types of behaviors and abilities related to autism spectrum disorder (ASD) were heritable (strongly influenced by gene variants passed down through a family) among autistic adults and their family members. These findings mean that these scores can be used in future studies interested in identifying specific genes and gene variants that are associated with different behaviors and abilities related with ASD.