A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management.

Digital Connectedness in the Jackson Heart Study: Cross-sectional Study.

BACKGROUND: Although new approaches for data collection, such as mobile technology and teleresearch, have demonstrated new opportunities for the conduct of more timely and less costly surveys in community-based studies, literature on the feasibility of conducing cardiovascular disease research using mobile health (mHealth) platforms among middle-aged and older African Americans has been limited. OBJECTIVE: The purpose of this study was to contribute to the knowledge regarding the penetrance of internet and mobile technologies, such as cellphones or smartphones in existing large cohort studies of cardiovascular disease. METHODS: A digital connectedness survey was conducted in the Jackson Heart Study (JHS), a Mississippi-based African American cohort study, as part of the annual follow-up calls with participants from July 2017 to February 2019. RESULTS: Of the 4024 participants contacted, 2564 (63.7%) completed the survey. Among survey respondents, 2262 (88.2%) reported use of internet or cellphone, and 1593 (62.1%) had a smartphone. Compared to nonusers (n=302), internet or cellphone users (n=2262) were younger (mean age 80.1, SD 8.0 vs 68.2, SD 11.3 years), more likely to be affluent (n=778, 40.1% vs n=39, 15.4%), and had greater than high school education (n=1636, 72.5% vs n=85, 28.1%). Internet or cellphone users were less likely to have cardiovascular disease history compared to nonusers (136/2262, 6.6% vs 41/302, 15.8%). The prevalence of current smoking and average BMI were similar between internet or cellphone users and nonusers. Among internet or cellphone users, 1316 (58.3%) reported use of email, 504 (22.3%) reported use of apps to track or manage health, and 1269 (56.1%) expressed interest in using JHS-developed apps. CONCLUSIONS: Our findings suggest that it is feasible to use mHealth technologies to collect survey data among African Americans already enrolled in a longitudinal study. Our findings also highlight the need for more efforts to reduce the age and education divide in access and use of internet and smartphones for tracking health and research in African American communities.

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults comprising 14 established US prospective cohort studies. Starting as early as 1971, investigators in the C4R cohort studies have collected data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R links this pre-coronavirus disease 2019 (COVID-19) phenotyping to information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute and postacute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and reflects the racial, ethnic, socioeconomic, and geographic diversity of the United States. C4R ascertains SARS-CoV-2 infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey conducted via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations and high-quality event surveillance. Extensive prepandemic data minimize referral, survival, and recall bias. Data are harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these data will be pooled and shared widely to expedite collaboration and scientific findings. This resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including postacute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term health trajectories.

Presence and transmission of mitochondrial heteroplasmic mutations in human populations of European and African ancestry.

We investigated the concordance of mitochondrial DNA heteroplasmic mutations (heteroplasmies) in 6745 maternal pairs of European (EA, n = 4718 pairs) and African (AA, n = 2027 pairs) Americans in whole blood. Mother-offspring pairs displayed the highest concordance rate, followed by sibling-sibling and more distantly-related maternal pairs. The allele fractions of concordant heteroplasmies exhibited high correlation (R2 = 0.8) between paired individuals. Discordant heteroplasmies were more likely to be in coding regions, be nonsynonymous or nonsynonymous-deleterious (p < 0.001). The number of deleterious heteroplasmies was significantly correlated with advancing age (20-44, 45-64, and ≥65 years, p-trend = 0.01). One standard deviation increase in heteroplasmic burden (i.e., the number of heteroplasmies carried by an individual) was associated with 0.17 to 0.26 (p < 1e - 23) standard deviation decrease in mtDNA copy number, independent of age. White blood cell count and differential count jointly explained 0.5% to 1.3% (p ≤ 0.001) variance in heteroplasmic burden. A genome-wide association and meta-analysis identified a region at 11p11.12 (top signal rs779031139, p = 2.0e - 18, minor allele frequency = 0.38) associated with the heteroplasmic burden. However, the 11p11.12 region is adjacent to a nuclear mitochondrial DNA (NUMT) corresponding to a 542 bp area of the D-loop. This region was no longer significant after excluding heteroplasmies within the 542 bp from the heteroplasmic burden. The discovery that blood mtDNA heteroplasmies were both inherited and somatic origins and that an increase in heteroplasmic burden was strongly associated with a decrease in average number of mtDNA copy number in blood are important findings to be considered in association studies of mtDNA with disease traits.

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.

Obesity and overall mortality: findings from the Jackson Heart Study.

BACKGROUND: Overall mortality has been reported to be lower among individuals classified as overweight/obese when compared with their normal weight counterparts ("obesity paradox") when obesity classification is based on the body mass index (BMI). One possible reason for this apparent paradox is that BMI is not a reliable measure of obesity-related risk as it does not differentiate fat mass from lean muscle mass or fat mass phenotypes. Waist circumference (WC), as a measure of central adiposity, may be a better indicator of obesity-related risk. We examined the association of overall mortality with BMI and with WC measures, including WC, waist-to-height ratio (WHtR) and waist-to-hip ratio (WHR). METHODS: Data from 3976 African American participants (551 deaths) in the Jackson Heart Study (JHS) were analyzed. Cox regression models were used to perform survival analysis. Obesity measures were analyzed as dichotomous (obese/non-obese) and continuous variables. Baseline covariates included age, sex and smoking status. RESULTS: Comparing obese to non-obese participants, adjusted hazard ratios (95% CI) for overall mortality were 1.14 (0.96, 1.35), 1.30 (1.07, 1.59), 1.02 (0.73, 1.41) and 1.45 (1.18, 1.79) when using BMI, WC, WHtR and WHR, respectively. For BMI, WC and WHtR, a J-shaped relationship was observed with overall mortality. For WHR, a monotonic increasing relationship was observed with overall mortality. CONCLUSIONS: In the JHS, we found that obesity as defined by WC and WHR was associated with an increased risk of overall and CVD mortality, while obesity defined by BMI was associated only with an increased risk of CVD mortality. WHR was the only obesity measure that showed a monotonic increasing relationship with overall and CVD mortality.

Joint modelling of longitudinal lipids and time to coronary heart disease in the Jackson Heart Study.

BACKGROUND: Multiple longitudinal responses together with time-to-event outcome are common in biomedical studies. There are several instances where the longitudinal responses are correlated with each other and at the same time each longitudinal response is associated with the survival outcome. The main purpose of this study is to present and explore a joint modeling approach for multiple correlated longitudinal responses and a survival outcome. The method will be illustrated using the Jackson Heart Study (JHS), which is one of the largest cardiovascular studies among African Americans. METHODS: Four longitudinal responses, i.e., total cholesterol (TC), high density lipoprotein (HDL) cholesterol, triglyceride (TG) and inflammation measured by high-sensitivity C-reactive protein (hsCRP); and time-to-coronary heart disease (CHD) were considered from the JHS. The repeated lipid and hsCRP measurements from a given subject overtime are likely correlated with each other and could influence the subject's risk for CHD. A joint modeling framework is considered. To deal with the high dimensionality due to the multiple longitudinal profiles, we use a pairwise bivariate model fitting approach that was developed in the context of multivariate Gaussian random effects models. The method is further explored through simulations. RESULTS: The proposed model performed well in terms of bias and relative efficiency. The JHS data analysis showed that lipid and hsCRP trajectories could exhibit interdependence in their joint evolution and have impact on CHD risk. CONCLUSIONS: We applied a unified and flexible joint modeling approach to analyze multiple correlated longitudinal responses and survival outcome. The method accounts for the correlation among the longitudinal responses as well as the association between each longitudinal response and the survival outcome at once. This helps to explore how the combination of multiple longitudinal trajectories could be related to the survival process.

Sequencing and imputation in GWAS: Cost-effective strategies to increase power and genomic coverage across diverse populations.

A key aim for current genome-wide association studies (GWAS) is to interrogate the full spectrum of genetic variation underlying human traits, including rare variants, across populations. Deep whole-genome sequencing is the gold standard to fully capture genetic variation, but remains prohibitively expensive for large sample sizes. Array genotyping interrogates a sparser set of variants, which can be used as a scaffold for genotype imputation to capture a wider set of variants. However, imputation quality depends crucially on reference panel size and genetic distance from the target population. Here, we consider sequencing a subset of GWAS participants and imputing the rest using a reference panel that includes both sequenced GWAS participants and an external reference panel. We investigate how imputation quality and GWAS power are affected by the number of participants sequenced for admixed populations (African and Latino Americans) and European population isolates (Sardinians and Finns), and identify powerful, cost-effective GWAS designs given current sequencing and array costs. For populations that are well-represented in existing reference panels, we find that array genotyping alone is cost-effective and well-powered to detect common- and rare-variant associations. For poorly represented populations, sequencing a subset of participants is often most cost-effective, and can substantially increase imputation quality and GWAS power.

Adherence and retention of African Americans in a randomized controlled trial with a yoga-based intervention: the effects of health promoting programs on cardiovascular disease risk study.

Objectives: Sedentary lifestyle is a risk factor for cardiovascular disease (CVD). Few alternative lifestyle interventions, such as yoga practice, focus on African Americans (AA), the population most vulnerable to CVD. Our objective is to compare the retention and adherence rates between yoga, walking, and health education interventions while providing information about the acceptance of various yoga regimens. Design: Three hundred seventy-five AA participants were recruited exclusively from an active cohort study and randomized into a 48-week study (24 weeks intervention, 24 weeks follow-up) with 5 health promotion interventions: high frequency yoga, moderate frequency yoga, low frequency yoga, guided walking, and health education. In addition to examining the separate yoga interventions, a pooled yoga intervention is considered for comparison to guided walking and health education. Participant retention, adherence, and vitals were monitored at each intervention session. Participants were also scheduled for four clinic visits throughout the study where blood panels, health behavior, and medication surveys were administered. Results: Of the 375 participants recruited, 31.7% did not complete the study. At baseline, in both the guided walking group and the high frequency yoga group, there were significant differences between those who completed the study and those who did not. Although intervention retention in the pooled yoga program (78.3%) was higher compared to the walking (60%) and education programs (74.3%) (p = 0.007), differences in post-intervention retention was not significant. Median adherence rates for the pooled yoga program exceeded rates for guided walking and education with moderate frequency yoga out performing high and low frequency yoga. Conclusion: Study-defined retention success rates were not reached by all health promotion programs. However, retention and adherence rates for the pooled yoga program show that older African Americans are receptive to participating in yoga-based health promotion practices.

Cardiovascular Disease Burden and Socioeconomic Correlates: Findings From the Jackson Heart Study.

BACKGROUND: Black persons have an excess burden of cardiovascular disease (CVD) compared with white persons. This burden persists after adjustment for socioeconomic status and other known CVD risk factors. This study evaluated the CVD burden and the socioeconomic gradient of CVD among black participants in the JHS (Jackson Heart Study). METHODS AND RESULTS: CVD burden was evaluated by comparing the observed prevalence of myocardial infarction, stroke, and hypertension in the JHS at baseline (2000-2004) with the expected prevalence according to US national surveys during a similar time period. The socioeconomic gradient of CVD was evaluated using logistic regression models. Compared with the national data, the JHS age- and sex-standardized prevalence ratios for myocardial infarction, stroke, and hypertension were 1.07 (95% CI, 0.90-1.27), 1.46 (95% CI, 1.18-1.78), and 1.51 (95% CI, 1.42-1.60), respectively, in men and 1.50 (95% CI, 1.27-1.76), 1.33 (95% CI, 1.12-1.57), and 1.43 (95% CI, 1.37-1.50), respectively, in women. A significant and inverse relationship was observed between socioeconomic status and CVD within the JHS cohort. The strongest and most consistent socioeconomic correlate after adjusting for age and sex was income for myocardial infarction (odds ratio: 3.53; 95% CI, 2.31-5.40) and stroke (odds ratio: 3.73; 95% CI, 2.32-5.97), comparing the poor and affluent income categories. CONCLUSIONS: Except for myocardial infarction in men, CVD burden in the JHS cohort was higher than expected. A strong inverse socioeconomic gradient of CVD was also observed within the JHS cohort.

Development of the Jackson Heart Study Coordinating Center.

The public health burden caused by cardiovascular disease (CVD) continues to adversely affect individuals in terms of cost, life expectancy, medical, pharmaceutical and hospital care. This burden has been excessive in the case of African Americans. The objective of this paper is to chronicle the procedures and processes that were implemented in the development of the Jackson Heart Study Coordinating Center. The Jackson Heart Study (JHS) is a population-based investigation of traditional and emerging risk factors that predict progression to CVD among African Americans. In response to the struggle against CVD, the Jackson Heart Study has convened a professional, technical, and administrative staff with specific competence in the operation of a coordinating center to handle the wide variety of areas related to CVD studies. The Jackson Heart Study Coordinating Center (JHSCC) was created to assure validity of the JHS findings and provide the resources necessary to meet comprehensive statistical needs (planning, implementing and monitoring data analysis); data management (designing, implementing and managing data collection and quality control), and administrative support. The JHSCC began with a commitment to support study functions in order to increase participant recruitment, retention and safety, meet regulatory requirements, prepare progress reports, and facilitate effective communication with the community and between all JHS centers. The JHSCC facilitates the efforts of the JHS scientists through the development and implementation of the study protocol. The efforts of the JHSCC have resulted in the successful preparation of scientific reports and manuscripts for publication and presentation of study findings and results. In summary, the JHSCC has emerged as an effective research mechanism that serves as the driving force behind the Jackson Heart Study activities.