Search

One mechanism by which genetic factors influence complex traits and diseases is altering gene expression. Direct measurement of gene expression in relevant tissues is rarely tenable; however, genetically regulated gene expression (GReX) can be estimated using prediction models derived from large multi-omic datasets. These approaches have led to the discovery of many gene-trait associations, but whether models derived from predominantly European ancestry (EA) reference panels can map novel associations in ancestrally diverse populations remains unclear. We applied PrediXcan to impute GReX in 51,520 ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) participants (35% African American, 45% Hispanic/Latino, 10% Asian, and 7% Hawaiian) across 25 key cardiometabolic traits and relevant tissues to identify 102 novel associations. We then compared associations in PAGE to those in a random subset of 50,000 White British participants from UK Biobank (UKBB(50k)) for height and body mass index (BMI). We identified 517 associations across 47 tissues in PAGE but not UKBB(50k), demonstrating the importance of diverse samples in identifying trait-associated GReX. We observed that variants used in PrediXcan models were either more or less differentiated across continental-level populations than matched-control variants depending on the specific population reflecting sampling bias. Additionally, variants from identified genes specific to either PAGE or UKBB(50k) analyses were more ancestrally differentiated than those in genes detected in both analyses, underlining the value of population-specific discoveries. This suggests that while EA-derived transcriptome imputation models can identify new associations in non-EA populations, models derived from closely matched reference panels may yield further insights. Our findings call for more diversity in reference datasets of tissue-specific gene expression.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

Groups of distantly related individuals who share a short segment of their genome identical-by-descent (IBD) can provide insights about rare traits and diseases in massive biobanks using IBD mapping. Clustering algorithms play an important role in finding these groups accurately and at scale. We set out to analyze the fitness of commonly used, fast and scalable clustering algorithms for IBD mapping applications. We designed a realistic benchmark for local IBD graphs and utilized it to compare the statistical power of clustering algorithms via simulating 2.3 million clusters across 850 experiments. We found Infomap and Markov Clustering (MCL) community detection methods to have high statistical power in most of the scenarios. They yield a 30% increase in power compared to the current state-of-art approach, with a 3 orders of magnitude lower runtime. We also found that standard clustering metrics, such as modularity, cannot predict statistical power of algorithms in IBD mapping applications. We extend our findings to real datasets by analyzing the Population Architecture using Genomics and Epidemiology (PAGE) Study dataset with 51,000 samples and 2 million shared segments on Chromosome 1, resulting in the extraction of 39 million local IBD clusters. We demonstrate the power of our approach by recovering signals of rare genetic variation in the Whole-Exome Sequence data of 200,000 individuals in the UK Biobank. We provide an efficient implementation to enable clustering at scale for IBD mapping for various populations and scenarios.Supplementary Information: The code, along with supplementary methods and figures are available at https://github.com/roohy/localIBDClustering.

Aims/hypothesis: Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA1c, that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA1c in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study. Methods: We conducted a GWAS of fasting glucose (n = 52,267), fasting insulin (n = 48,395) and HbA1c (n = 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS meta-analyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci. Results: Four novel associations were identified (p < 5 × 10−9), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known GCK locus and for fasting insulin at the known PPP1R3B locus in transethnic meta-analysis. Conclusions/interpretation: Our findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations. Data availability: Full summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog (https://www.ebi.ac.uk/gwas/downloads/summary-statistics).

The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Background Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented. Results We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations. Conclusions Our results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits.

Background Concurrent variation in adiposity and inflammation suggests potential shared functional pathways and pleiotropic disease underpinning. Yet, exploration of pleiotropy in the context of adiposity-inflammation has been scarce, and none has included self-identified Hispanic/Latino populations. Given the high level of ancestral diversity in Hispanic American population, genetic studies may reveal variants that are infrequent/monomorphic in more homogeneous populations. Methods Using multi-trait Adaptive Sum of Powered Score (aSPU) method, we examined individual and shared genetic effects underlying inflammatory (CRP) and adiposity-related traits (Body Mass Index [BMI]), and central adiposity (Waist to Hip Ratio [WHR]) in HLA participating in the Population Architecture Using Genomics and Epidemiology (PAGE) cohort (N = 35,871) with replication of effects in the Cameron County Hispanic Cohort (CCHC) which consists of Mexican American individuals. Results Of the > 16 million SNPs tested, variants representing 7 independent loci were found to illustrate significant association with multiple traits. Two out of 7 variants were replicated at statistically significant level in multi-trait analyses in CCHC. The lead variant on APOE (rs439401) and rs11208712 were found to harbor multi-trait associations with adiposity and inflammation. Conclusions Results from this study demonstrate the importance of considering pleiotropy for improving our understanding of the etiology of the various metabolic pathways that regulate cardiovascular disease development.

Animal studies have revealed gut microbial and metabolic pathways of blood pressure (BP) regulation, yet few epidemiological studies have collected microbiota and metabolomics data in the same individuals. In a population-based, Chinese cohort who did not report antihypertension medication use (30–69 years, 54% women), thus minimizing BP treatment effects, we examined multivariable-adjusted (eg, diet, physical activity, smoking, kidney function), cross-sectional associations between measures of gut microbiota (16S rRNA [ribosomal ribonucleic acid], N=1003), and plasma metabolome (liquid chromatography-mass spectrometry, N=434) with systolic (SBP, mean [SD]=126.0 [17.4] mm Hg) and diastolic BP (DBP [80.7 (10.7) mm Hg]). We found that the overall microbial community assessed by principal coordinate analysis varied by SBP and DBP (permutational multivariate ANOVA P P P

Background: There is increasing evidence that sodium consumption alters the gut microbiota and host metabolome in murine models and small studies in humans. However, there is a lack of population-based studies that capture large variations in sodium consumption as well as potassium consumption. Objective: We examined the associations of energy-adjusted dietary sodium (milligrams/kilocalorie), potassium, and sodium-to-potassium (Na/K) ratio with the microbiota and plasma metabolome in a well-characterized Chinese cohort with habitual excessive sodium and deficient potassium consumption. Methods: We estimated dietary intakes from 3 consecutive validated 24-h recalls and household inventories. In 2833 adults (18-80 y old, 51.2% females), we analyzed microbial (genus-level 16S ribosomal RNA) between-person diversity, using distance-based redundancy analysis (dbRDA), and within-person diversity and taxa abundance using linear regression, accounting for geographic variation in both. In a subsample (n = 392), we analyzed the overall metabolome (dbRDA) and individual metabolites (linear regression). P values for specific taxa and metabolites were false discovery rate adjusted (q-value). Results: Sodium, potassium, and Na/K ratio were associated with microbial between-person diversity (dbRDA P < 0.01) and several specific taxa with large geographic variation, including pathogenic Staphylococcus and Moraxellaceae, and SCFA-producing Phascolarctobacterium and Lachnospiraceae (q-value < 0.05). For example, sodium and Na/K ratio were positively associated with Staphylococcus and Moraxellaceae in Liaoning, whereas potassium was positively associated with 2 genera from Lachnospiraceae in Shanghai. Additionally, sodium, potassium, and Na/K ratio were associated with the overall metabolome (dbRDA P ≤ 0.01) and several individual metabolites, including butyrate/isobutyrate and gut-derived phenolics such as 1,2,3-benzenetriol sulfate, which was negatively associated with sodium in Guizhou (q-value < 0.05). Conclusions: Our findings suggest that sodium and potassium consumption is associated with taxa and metabolites that have been implicated in cardiometabolic health, providing insights into the potential roles of gut microbiota and host metabolites in the pathogenesis of sodium- and potassium-associated diseases. More studies are needed to confirm our results.

Mitigating age-related disease and disability presents challenges. Physical activity (PA) may be influential for prolonging health and functioning, warranting characterization of its patterns over the life course in population-based data. With the availability of up to three self-reported assessments of past year leisure-time PA (LTPA) over multiple decades in 15,036 participants (26% African American; 55% women; mean baseline age=54; median follow-up=23 years) from the Atherosclerosis Risk in Communities (ARIC) Study sampled from four U.S. communities, race-sex-stratified trajectories of average weekly intensity (metabolic equivalent of task (MET)), duration (hours), and energy expenditure or volume (MET-h) of LTPA were developed from age 45 to 90 using joint models to accommodate expected non-ignorable attrition. Declines in weekly LTPA intensity, duration, and volume from age 70 to 90 were observed in white women (2.9 to 1.2 MET; 2.5 to 0.6 h; 11.1 to 2.6 MET-h), white men (2.5 to 1.0 MET; 3.5 to 1.8 h; 15.5 to 6.4 MET-h), African American women (2.5 to 2.4 MET; 0.8 to 0.1 h; 6.7 to 6.0 MET-h), and African American men (2.3 to 1.4 MET; 1.5 to 0.6 h; 8.0 to 2.3 MET-h). These data reveal population-wide shifts towards less active lifestyles in older adulthood.

Background Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population. Results We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic population contained at least one significant association signal (p 5%) across all ancestral populations. Nineteen additional independent association signals were identified at seven known loci (HFE, KIT, HBS1L/MYB, CITED2/FILNC1, ABO, HBA1/2, and PLIN4/5). For example, the HBA1/2 locus contained 14 conditionally independent association signals, 11 of which were previously unreported and are specific to African and Amerindian ancestries. One variant in this region was common in all ancestries, but exhibited a narrower LD block in African Americans than European Americans or Hispanics/Latinos. GTEx eQTL analysis of all independent lead SNPs yielded 31 significant associations in relevant tissues, over half of which were not at the gene immediately proximal to the lead SNP. Conclusion This work identified seven loci containing multiple independent association signals for RBC traits using a combined-phenotype approach, which may improve discovery in genetically correlated traits. Highly complex genetic architecture at the HBA1/2 locus was only revealed by the inclusion of African Americans and Hispanics/Latinos, underscoring the continued importance of expanding large GWAS to include ancestrally diverse populations.

Objective This study aimed to understand how an increase in abdominal adiposity relative to overall adiposity is associated with blood pressure (BP) change. Methods A sex-stratified mixed linear model was used to examine the association (95% CI) between annual changes in waist circumference (WC) and systolic blood pressure and diastolic blood pressure, estimated from two to eight repeated measures across the 1993-2015 China Health and Nutrition Survey, among 5,742 men and 5,972 women (18-66 years) with no history of antihypertension medication use. Results The association between annual WC change and BP change remained statistically significant but was attenuated after controlling for annual BMI change, regardless of baseline abdominal obesity or overweight status. Each 10-cm annual WC gain in men and women was associated with a 0.98-mm Hg (95% CI: 0.61-1.35) and a 0.97-mm Hg (95% CI: 0.62-1.32) annual increase in systolic blood pressure and a 1.13-mm Hg (95% CI: 0.87-1.38) and a 0.74-mm Hg (95% CI: 0.51-0.97) annual increase in diastolic blood pressure, respectively, independent of annual BMI change. Conclusions WC gain may elevate BP even in the absence of BMI gain. BP management that addresses only BMI gain could overlook individuals at risk of elevated BP who have increased WC but not BMI.

Background Research examining the role of obesity in cardiovascular disease (CVD) often fails to adequately consider heterogeneity in obesity severity, distribution, and duration. Methods and Results We here use multivariate latent class mixed models in the biracial Atherosclerosis Risk in Communities study (N=14 514; mean age=54 years; 55% female) to associate obesity subclasses (derived from body mass index, waist circumference, self‐reported weight at age 25, tricep skinfold, and calf circumference across up to four triennial visits) with total mortality, incident CVD, and CVD risk factors. We identified four obesity subclasses, summarized by their body mass index and waist circumference slope as decline (4.1%), stable/slow decline (67.8%), moderate increase (24.6%), and rapid increase (3.6%) subclasses. Compared with participants in the stable/slow decline subclass, the decline subclass was associated with elevated mortality (hazard ratio [HR] 1.45, 95% CI 1.31, 1.60, P P P =0.0002), and coronary heart disease (HR 1.36, 95% CI 1.14, 1.63, P =0.0008), adjusting for baseline body mass index and CVD risk factor profile. The moderate increase latent class was not associated with any significant differences in CVD risk as compared to the stable/slow decline latent class and was associated with a lower overall risk of mortality (HR 0.85, 95% CI 0.80, 0.90, P P =0.004). Conclusions Consideration of heterogeneity and longitudinal changes in obesity measures is needed in clinical care for a more precision‐oriented view of CVD risk.

The first phase of Chile's Law of Food Labelling and Advertising showed important declines in the sugar content of packaged foods, but it is unknown whether the law led to an increase in nonnutritive sweetener (NNS) intake, particularly among preschool children.Estimate the changes in preschoolers' NNS intake after the first phase of the Chilean law.We used 24-h dietary recalls collected in 2016 (pre-law) and 2017 (post-law) from a cohort of preschoolers (n = 875). The primary caretaker was the respondent of the recalls. Information on NNS was obtained from nutrition facts panels collected annually and linked to dietary data. We used logistic regression to estimate the changes in the proportion of preschoolers who consume NNS and two-part models to estimate the changes in mean intake. We determined the percentage of children that surpassed the acceptable daily intake (ADI) of each NNS using the National Cancer Institute method.The proportion of consumers of at least one NNS increased from 77.9% to 92.0% (p-value 0.01). The mean intake increased for sucralose, aspartame, acesulfame-K and steviol glycosides (+20.3, +15.1, +6.1 and +3.3 mg/day, respectively). In addition, NNS dietary sources changed for sucralose and steviol glycosides, becoming industrialized juices and dairy beverages more relevant while tabletop NNS became less relevant. None of the children surpassed the ADI.NNS intake increased in preschoolers after the first phase of a national policy that promoted sugar reformulation.

The ability to identify segments of genomes identical-by-descent (IBD) is a part of standard workflows in both statistical and population genetics. However, traditional methods for finding local IBD across all pairs of individuals scale poorly leading to a lack of adoption in very large-scale datasets. Here, we present iLASH, an algorithm based on similarity detection techniques that shows equal or improved accuracy in simulations compared to current leading methods and speeds up analysis by several orders of magnitude on genomic datasets, making IBD estimation tractable for millions of individuals. We apply iLASH to the PAGE dataset of ~52,000 multi-ethnic participants, including several founder populations with elevated IBD sharing, identifying IBD segments in ~3 minutes per chromosome compared to over 6 days for a state-of-the-art algorithm. iLASH enables efficient analysis of very large-scale datasets, as we demonstrate by computing IBD across the UK Biobank (~500,000 individuals), detecting 12.9 billion pairwise connections., Traditional methods to identify genomic regions identical-by-descent (IBD) do not scale well to biobank-level datasets. Here, the authors describe a new IBD algorithm, iLASH, which uses LocAlity-Sensitive Hashing to provide rapid IBD estimation when applied to the PAGE and UK Biobank datasets.

BACKGROUND Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. METHODS We conducted a case–control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal ( RESULTS The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10−8) and in the race-combined analysis (P = 1.5 × 10−9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6–0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

Genome-wide association studies have been successful mapping loci for individual phenotypes, but few studies have comprehensively interrogated evidence of shared genetic effects across multiple phenotypes simultaneously. Statistical methods have been proposed for analyzing multiple phenotypes using summary statistics, which enables studies of shared genetic effects while avoiding challenges associated with individual-level data sharing. Adaptive tests have been developed to maintain power against multiple alternative hypotheses because the most powerful single-alternative test depends on the underlying structure of the associations between the multiple phenotypes and a single nucleotide polymorphism (SNP). Here we compare the performance of six such adaptive tests: two adaptive sum of powered scores (aSPU) tests, the unified score association test (metaUSAT), the adaptive test in a mixed-models framework (mixAda) and two principal-component-based adaptive tests (PCAQ and PCO). Our simulations highlight practical challenges that arise when multivariate distributions of phenotypes do not satisfy assumptions of multivariate normality. Previous reports in this context focus on low minor allele count (MAC) and omit the aSPU test, which relies less than other methods on asymptotic and distributional assumptions. When these assumptions are not satisfied, particularly when MAC is low and/or phenotype covariance matrices are singular or nearly singular, aSPU better preserves type I error, sometimes at the cost of decreased power. We illustrate this trade-off with multiple phenotype analyses of six quantitative electrocardiogram traits in the Population Architecture using Genomics and Epidemiology (PAGE) study.

US Latinos, a growing, aging population, are disproportionately burdened by cognitive decline and dementia. Identification of modifiable risk factors is needed for interventions aimed at reducing risk. Broad sociocultural context may illuminate complex etiology among culturally diverse Latinos. Among 1,418 older (≥60 years), low–socioeconomic position (SEP) Latinos (predominantly of Mexican descent) in Sacramento, California, we examined whether US acculturation was associated with cognitive performance, cognitive decline, and dementia/ cognitive impairment without dementia over a 10-year period and whether education modified the associations (Sacramento Area Latino Study on Aging, 1998–2008). Analyses used linear mixed models, competing-risk regression, and inverse probability of censoring weights for attrition. Participants with high US acculturation had better cognitive performance (0.21 fewer cognitive errors at grand-mean-centered age 70 years) than those with low acculturation after adjustment for sociodemographic factors, practice effects, and survey language. Results may have been driven by cultural language use rather than identity factors (e.g., ethnic identity, interactions). Rate of cognitive decline and risk of dementia/cognitive impairment without dementia did not differ by acculturation, regardless of education (β = 0.00 (standard error, 0.00) and hazard ratio = 0.81 (95% confidence interval: 0.49, 1.35), respectively). High US acculturation was associated with better cognitive performance among these older, low-SEP Latinos. Acculturation may benefit cognition when SEP is low. Future studies should incorporate extended longitudinal assessments among more diverse groups.

Background: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci. Methods: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test. Results: We identified 6 novels ( CD36, PITX2, EMB, ZNF592, YPEL2 , and BC043580 ) and 87 known loci (adaptive sum of powered score test P −9 ). Lead single-nucleotide polymorphism rs3211938 at CD36 was common in Blacks (minor allele frequency=10%), near monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other 5 novel loci were observed when evaluating the contiguous but not the composite electrocardiographic traits. Combined phenotype testing did not identify novel electrocardiographic loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci. Conclusions: Despite including one-third as many participants as published electrocardiographic trait genome-wide association studies, our study identified 6 novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing genome-wide association studies.

Epidemiological studies suggest a positive association between obesity and fecal short-chain fatty acids (SCFAs) produced by microbial fermentation of dietary carbohydrates, while animal models suggest increased energy harvest through colonic SCFA production in obesity. However, there is a lack of human population-based studies with dietary intake data, plasma SCFAs, gut microbial, and anthropometric data. In 490 Chinese adults aged 30&ndash, 68 years, we examined the associations between key plasma SCFAs (butyrate/isobutyrate, isovalerate, and valerate measured by non-targeted plasma metabolomics) with body mass index (BMI) using multivariable-adjusted linear regression. We then assessed whether overweight (BMI &ge, 24 kg/m2) modified the association between dietary-precursors of SCFAs (insoluble fiber, total carbohydrates, and high-fiber foods) with plasma SCFAs. In a sub-sample (n = 209) with gut metagenome data, we examined the association between gut microbial SCFA-producers with BMI. We found positive associations between butyrate/isobutyrate and BMI (p-value &lt, 0.05). The associations between insoluble fiber and butyrate/isobutyrate differed by overweight (p-value &lt, 0.10). There was no statistical evidence for an association between microbial SCFA-producers and BMI. In sum, plasma SCFAs were positively associated with BMI and that the colonic fermentation of fiber may differ for adults with versus without overweight.

Background Excess adiposity, which affects 69% of US adults, increases coronary heart disease ( CHD ) risk in an association that manifests below conventional obesity cut points. The population‐level impact on CHD risk that is attainable through modest adiposity reductions in populations is not well characterized. We estimated the effect of hypothetical reductions in both body mass index ( BMI ) and waist circumference ( WC ) on CHD incidence. Methods and Results The study population included 13 610 ARIC (Atherosclerosis Risk in Communities) participants. Our hypothetical reduction in BMI or WC was applied relative to the temporal trend, with no hypothetical reduction among those with BMI >24 or WC >88 cm, respectively. This threshold for hypothetical reduction is near the clinical guidelines for excess adiposity. CHD risk differences compared the hypothetical reduction with no reduction. Sensitivity analysis was conducted to estimate the effect of applying the hypothetical BMI reduction at the established overweight cut point of 25. Cumulative 12‐year CHD incidence with no intervention was 6.3% (95% CI, 5.9–6.8%). Risk differences following the hypothetical BMI and WC reductions were −0.6% (95% CI, −1.0% to −0.1%) and −1.0% (95% CI, −1.4% to −0.5%), respectively. These results were robust for the sensitivity analyses. Consequently, we estimated that this hypothetical reduction of 5% in BMI and WC, respectively, could have prevented 9% and 16%, respectively, of the CHD events occurring in this study population over 12 years, after adjustment for established CHD risk factors. Conclusions Meaningful CHD risk reductions could derive from modest reductions in adiposity attainable through lifestyle modification.

Background Experimental and observational research has suggested the potential for increased type 2 diabetes (T2D) risk among populations taking statins for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). However, few studies have directly compared statin-associated benefits and harms or examined heterogeneity by population subgroups or assumed treatment effect. Thus, we compared ASCVD risk reduction and T2D incidence increases across 3 statin treatment guidelines or recommendations among adults without a history of ASCVD or T2D who were eligible for statin treatment initiation. Methods and findings Simulations were conducted using Markov models that integrated data from contemporary population-based studies of non-Hispanic African American and white adults aged 40–75 years with published meta-analyses. Statin treatment eligibility was determined by predicted 10-year ASCVD risk (5%, 7.5%, or 10%). We calculated the number needed to treat (NNT) to prevent one ASCVD event and the number needed to harm (NNH) to incur one incident case of T2D. The likelihood to be helped or harmed (LHH) was calculated as ratio of NNH to NNT. Heterogeneity in statin-associated benefit was examined by sex, age, and statin-associated T2D relative risk (RR) (range: 1.11–1.55). A total of 61,125,042 U.S. adults (58.5% female; 89.4% white; mean age = 54.7 years) composed our primary prevention population, among whom 13–28 million adults were eligible for statin initiation. Overall, the number of ASCVD events prevented was at least twice as large as the number of incident cases of T2D incurred (LHH range: 2.26–2.90). However, the number of T2D cases incurred surpassed the number of ASCVD events prevented when higher statin-associated T2D RRs were assumed (LHH range: 0.72–0.94). In addition, females (LHH range: 1.74–2.40) and adults aged 40–50 years (LHH range: 1.00–1.14) received lower absolute benefits of statin treatment compared with males (LHH range: 2.55–3.00) and adults aged 70–75 years (LHH range: 3.95–3.96). Projected differences in LHH by age and sex became more pronounced as statin-associated T2D RR increased, with a majority of scenarios projecting LHHs < 1 for females and adults aged 40–50 years. This study’s primary limitation was uncertainty in estimates of statin-associated T2D risk, highlighting areas in which additional clinical and public health research is needed. Conclusions Our projections suggest that females and younger adult populations shoulder the highest relative burden of statin-associated T2D risk., Joseph Engada and colleagues model the reduction in cardiovascular disease risk across three statin treatment guidelines., Author summary Why was this study done? Statins are a widely prescribed medication used to prevent atherosclerotic cardiovascular disease (ASCVD). Past research has suggested the potential for increased type 2 diabetes (T2D) risk among populations taking statins. Few studies have compared statin-associated benefits (ASCVD prevention) and statin-associated harms (increased T2D incidence) using different statin treatment guidelines and recommendations in contemporary U.S. populations or by population subgroups defined by age and sex. What did the researchers do and find? We developed a simulation model to compare statin treatment guidelines and recommendations in a U.S. population without T2D or a previous ASCVD event by synthesizing data from contemporary population-based studies with published meta-analyses. Using the model, our projections suggested that the number of ASCVD events prevented was at least twice as large as the number of incident cases of T2D incurred. However, the number of T2D cases incurred surpassed the number of ASCVD events prevented when higher statin-associated T2D relative risks (RRs) were assumed. Our models also suggest that females and the youngest adults received lower absolute benefits of statin treatment compared with males and the oldest adults. Projected differences by age and sex also were more pronounced as the effect of statins on T2D was increased. For females and younger populations, a majority of these scenarios suggested that the number of new T2D cases was greater than the number of ASCVD events prevented. What do these findings mean? Our projections suggested that females and younger adult populations shoulder the highest relative burden of statin-associated T2D risk. Clinical and public health research to more precisely quantify statin’s effects on T2D is needed given the sensitivity of projections to this simulation parameter.

Publisher's version (útgefin grein), The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p

Background Evidence shows that dietary factors play an important role in blood pressure. However, there is no clear understanding of whether hypertension diagnosis is associated with dietary modifications. The aim of this study is to estimate the longitudinal association between hypertension diagnosis and subsequent changes (within 2–4 years) in dietary sodium, potassium, and sodium‐potassium (Na/K) ratio. Methods and Results We included adults (18–75 years, n=16 264) from up to 9 waves (1991–2015) of the China Health and Nutrition Survey. Diet data were collected using three 24‐hour dietary recalls and a household food inventory. We used fixed‐effects models to estimate the association between newly self‐reported diagnosed hypertension and subsequent within‐individual changes in sodium, potassium, and Na/K ratio. We also examined changes among couples and at the household level. Results suggest that on average, men who were diagnosed with hypertension decreased their sodium intake by 251 mg/d and their Na/K ratio by 0.19 within 2 to 4 years after diagnosis ( P P Conclusions Our findings suggest that hypertension diagnosis for a man may result in modest dietary improvements for him, his wife, and other household members. Yet, diagnosis for a woman does not seem to result in dietary changes for her or her household members.

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10−8) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10−8) and multi-trait analysis (P = 2.9 × 10−9) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P

Background Metastases play a role in about 90% of cancer deaths. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells might provide diagnostic information about the likelihood that cancer cells have detached from the primary tumor. Used together with established diagnostic tests of detachment—lymph node evaluation and radiologic imaging—EMT marker measurements might improve the ability of clinicians to assess the patient’s risk of metastatic disease. Translation of EMT markers to clinical use has been hampered by a lack of valid analyses of clinically-informative parameters. Here, we demonstrate a rigorous approach to estimating the sensitivity, specificity, and prediction increment of an EMT marker to assess cancer cell detachment from primary tumors. Methods We illustrate the approach using immunohistochemical measurements of the EMT marker E-cadherin in a set of colorectal primary tumors from a population-based prospective cohort in North Carolina. Bayesian latent class analysis was used to estimate sensitivity and specificity in a setting of multiple imperfect diagnostic tests and no gold standard. Risk reclassification analysis was used to assess the extent to which addition of the marker to the panel of established diagnostic tests would improve mortality prediction. We explored how changing the latent class conditional dependence assumptions and definition of marker positivity would impact the results. Results All diagnostic accuracy and prediction increment statistics varied with the choice of cut point to define marker positivity. When comparing different definitions of marker positivity to each other, numerous trade-offs were observed in terms of sensitivity, specificity, predictive discrimination, and prediction model calibration. We then discussed several implementation considerations and the plausibility of analytic assumptions. Conclusions The approaches presented here can be extended to any EMT marker, to most forms of cancer, and to different kinds of EMT marker measurements, such as RNA or gene methylation data. These methods provide valid, clinically-informative assessment of whether and how to use a given EMT marker to refine tumor staging and consequent treatment decisions. Electronic supplementary material The online version of this article (10.1186/s12885-017-3964-3) contains supplementary material, which is available to authorized users.

ObjectivePR interval (PR) is a heritable electrocardiographic measure of atrial and atrioventricular nodal conduction. Changes in PR duration may be associated with atrial fibrillation, heart failure and all-cause mortality. Hispanic/Latino populations have high burdens of cardiovascular morbidity and mortality, are highly admixed and represent exceptional opportunities for novel locus identification. However, they remain chronically understudied. We present the first genome-wide association study (GWAS) of PR in 14 756 participants of Hispanic/Latino ancestry from three studies.MethodsStudy-specific summary results of the association between 1000 Genomes Phase 1 imputed single-nucleotide polymorphisms (SNPs) and PR assumed an additive genetic model and were adjusted for global ancestry, study centre/region and clinical covariates. Results were combined using fixed-effects, inverse variance weighted meta-analysis. Sequential conditional analyses were used to identify independent signals. Replication of novel loci was performed in populations of Asian, African and European descent. ENCODE and RoadMap data were used to annotate results.ResultsWe identified a novel genome-wide association (P−8) with PR at ID2 (rs6730558), which replicated in Asian and European populations (PConclusionsOur results suggest that genetic determinants of PR are consistent across race/ethnicity, but extending studies to admixed populations can identify novel associations, underscoring the importance of conducting genetic studies in diverse populations.

Background Although time–domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multiethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized. Objective The purpose of this study was to conduct a genome-wide association study of heart rate (HR) and its variability in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n = 13,767). Methods We estimated HR (bpm), standard deviation of normal-to-normal interbeat intervals (SDNN, ms), and root mean squared difference in successive, normal-to-normal interbeat intervals (RMSSD, ms) from resting, standard 12-lead ECGs. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P Results Two genome-wide significant SNPs replicated in a European ancestry cohort, 1 one for RMSSD (rs4963772; chromosome 12) and another for SDNN (rs12982903; chromosome 19). A suggestive SNP for HR (rs236352; chromosome 6) replicated in an African-American cohort. Functional annotation of replicated SNPs in cardiac and neuronal tissues identified potentially causal variants and mechanisms. Conclusion This first genome-wide association study of HRV and HR in Hispanics/Latinos underscores the potential for even modestly sized samples of non-European ancestry to inform the genetic epidemiology of complex traits.

Background: Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Moreover, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed. Methods: To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including n = 229 African American and n = 381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, n = 922 European ancestry participants, whole blood). We then performed a transcriptome-wide association study (TWAS) for platelet count, hemoglobin, hematocrit, and white blood cell count in African (n = 27,955) and Hispanic/Latino (n = 28,324) ancestry participants. Results: Our results revealed 24 suggestive signals (p < 1 × 10−4) that were conditionally distinct from known GWAS identified variants and successfully replicated these signals in European ancestry subjects from UK Biobank. We found modestly improved correlation of predicted and measured gene expression in an independent African American cohort (the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 802), lymphoblastoid cell lines) using the larger DGN reference panel; however, some genes were well predicted using MESA but not DGN. Conclusions: These analyses demonstrate the importance of performing TWAS and other genetic analyses across diverse populations and of balancing sample size and ancestry background matching when selecting a TWAS reference panel.

Key Points Question Did US mortality trends during 1999-2011 and 2011-2018 differ for obesity-associated cancers and cancers not associated with obesity? Findings Using 20 years of cross-sectional mortality data, this study found that after 2011, mortality improvements accelerated for cancers not associated with obesity. In contrast, mortality improvements decelerated for obesity-associated cancers, paralleling recent trends for heart disease mortality. Meaning The study results are consistent with the hypothesis that the obesity epidemic may have been associated with slowed improvement in obesity-associated cancer mortality., Importance Heart disease and cancer are the 2 major diseases associated with mortality risk in the United States. Four decades of improvements in heart disease mortality slowed after 2011; this slowing has been associated with the obesity epidemic. The same pattern has not been observed for total cancer mortality. However, trends in total cancer mortality may obscure patterns specific to obesity-associated cancers. Objective To investigate whether trends in obesity-associated cancer mortality mirror the slowed mortality improvements observed for heart disease associated with the obesity epidemic. Design, Setting, and Participants This cross-sectional study compared US mortality trends for International Statistical Classification of Diseases and Related Health Problems, Tenth Revision–defined cancer (total cancer, obesity-associated cancer, and cancer not associated with obesity) and heart disease deaths from January 1, 1999, to December 31, 2018. Data were included on decedents with complete information on the underlying cause of death, age, sex, race, and ethnicity. Exposures Changes in age-adjusted cause-specific mortality rates between 1999-2011 and 2011-2018 were compared. Main Outcomes and Measures Annual relative rates of change in age-adjusted mortality rates (AAMRs) in the overall population and stratified by sex, race, and ethnicity were estimated using Poisson regression. Differences in AAMR annual relative rates of change before and after 2011 were evaluated using Wald tests. Results A total of 50 163 483 decedents met the inclusion criteria (50.1% female decedents, 79.9% non-Hispanic White decedents, and 11.7% non-Hispanic Black decedents; mean [SD] age, 72.8 [18.5] years). In contrast with heart disease mortality, for which improvements slowed between 1999-2011 and 2011-2018, decreases in total cancer AAMR relative change accelerated between 1999-2011 (−1.48 [95% CI, −1.43 to −1.52]) and 2011-2018 (−1.77 [95% CI, −1.67 to −1.86]) (P, This cross-sectional study investigates whether trends in obesity-associated cancer mortality mirror the slowed mortality improvements observed for heart disease associated with the obesity epidemic.

An association between periodontitis and nonalcoholic fatty liver disease (NAFLD) has been reported by experimental animal and epidemiologic studies. This study investigated whether circulating levels of serum C-reactive protein (CRP) and a weighted genetic CRP score representing markers of inflammatory burden modify the association between periodontitis and NAFLD. Data came from 2,481 participants of the Study of Health in Pomerania who attended baseline examination that occurred between 1997 and 2001. Periodontitis was defined as the percentage of sites (0%, 3 mg/L. Periodontitis was positively associated with higher prevalence odds of NAFLD, and this relationship was modified by serum CRP levels.

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11–34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations., Author summary Admixed African and Hispanic/Latino populations remain understudied in genetic studies of complex diseases. These populations have more complex linkage disequilibrium (LD) structure that can impair mapping of variants. Genotype imputation represents an approach to improve genome coverage, especially for rare or ancestry-specific variation; however, these understudied populations also have smaller relevant imputation reference panels. In this study, we leveraged >100,000 phased sequences generated from the multi-ethnic NHLBI TOPMed project for imputation in ~21,600 individuals of African ancestry (AAs) and ~21,700 Hispanics/Latinos. We demonstrated substantially higher imputation quality for low frequency and rare variants in comparison to the 1000 Genomes Project and Haplotype Reference Consortium reference panels. Analysis of quantitative hematological traits led to the discovery of associations with two rare variants in the HBB gene; one of these variants was replicated in an independent sample, and the other is known to cause anemia in the homozygous state. By comparison, the same HBB variants would not have been genome-wide significant using current reference panels due to lower imputation quality. Our findings demonstrate the power of TOPMed whole genome sequencing data for imputation and subsequent association analysis in admixed African and Hispanic/Latino populations.

Acculturation may shape the disproportionate burden of poor sleep among Latinos in the United States. Existing studies are limited by unidimensional acculturation proxies that are incapable of capturing cultural complexities across generations. Understanding how acculturation relates to sleep may lead to the identification of modifiable intervention targets. We used multivariable regression and latent class methods to examine cross-sectional associations between a validated multidimensional scale of US acculturation and self-reported poor sleep measures. We analyzed an intergenerational cohort: first-generation (GEN1) older Latinos (Sacramento Area Latino Study on Aging; N = 1,716; median age: 69.5) and second-generation (GEN2) middle-aged offspring and relatives of GEN1 (Niños Lifestyle and Diabetes Study; N = 670; median age: 54.0) in Sacramento, California. GEN1 with high US acculturation, compared with high acculturation towards another origin/ancestral country, had less restless sleep (prevalence ratio [PR] [95% confidence interval (CI)]: 0.67 [0.54, 0.84]) and a higher likelihood of being in the best sleep class than the worst (OR [95% CI]: 1.62 [1.09, 2.40]), but among nonmanual occupations, high intergenerational US acculturation was associated with more general fatigue (PR [95% CI: 1.86 [1.11, 3.10]). GEN2 with high intergenerational US acculturation reported shorter sleep (PR [95% CI]: 2.86 [1.02, 7.99]). High US acculturation shaped sleep differentially by generation, socioeconomic context, and intergenerational acculturative status. High US acculturation was associated with better sleep among older, lower socioeconomic Latinos, but with shorter sleep duration among middle-aged, higher socioeconomic Latinos; results also differed by parental acculturation status. Upon replication, future studies should incorporate prospective and intergenerational designs to uncover sociobehavioral pathways by which acculturation may shape sleep to ultimately inform intervention efforts.

BackgroundThe electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.MethodsWe performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.ResultsWe identified six loci associated with QRS (PConclusionsOur QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.

We performed a hypothesis-generating phenome-wide association study (PheWAS) to identify and characterize cross-phenotype associations, where one SNP is associated with two or more phenotypes, between thousands of genetic variants assayed on the Metabochip and hundreds of phenotypes in 5,897 African Americans as part of the Population Architecture using Genomics and Epidemiology (PAGE) I study. The PAGE I study was a National Human Genome Research Institute-funded collaboration of four study sites accessing diverse epidemiologic studies genotyped on the Metabochip, a custom genotyping chip that has dense coverage of regions in the genome previously associated with cardio- metabolic traits and outcomes in mostly European-descent populations. Here we focus on identifying novel phenome-genome relationships, where SNPs are associated with more than one phenotype. To do this, we performed a PheWAS, testing each SNP on the Metabochip for an association with up to 273 phenotypes in the participating PAGE I study sites. We identified 133 putative pleiotropic variants, defined as SNPs associated at an empirically derived p-value threshold of p

AIMS To conduct a meta-analysis of statin-associated type 2 diabetes mellitus (T2D) risk among randomized controlled trials (RCTs) and observational studies (OBSs), excluding studies conducted among secondary prevention populations. METHODS Studies were identified by searching PubMed (1994-present) and EMBASE (1994-present). Articles had to meet the following criteria: (1) follow-up >one year; (2) >50% of participants free of clinically diagnosed ASCVD; (3) adult participants ≥30 years old; (4) reported statin-associated T2D effect estimates; and (5) quantified precision using 95% confidence interval. Data were pooled using random-effects model. RESULTS We identified 23 studies (35% RCTs) of n = 4,012,555 participants. OBS participants were on average younger (mean difference = 6.2 years) and had lower mean low-density lipoprotein cholesterol (LDL-C, mean difference = 20.6 mg/dL) and mean fasting plasma glucose (mean difference = 5.2 mg/dL) compared to RCT participants. There was little evidence for publication bias (P > 0.1). However, evidence of heterogeneity was observed overall and among OBSs and RCTs (PCochran =

US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We simultaneously estimated population-structure principal components (PCs) robust to familial relatedness and pairwise kinship coefficients (KCs) robust to population structure, admixture, and Hardy-Weinberg departures. The PCs revealed substantial genetic differentiation within and among six self-identified background groups (Cuban, Dominican, Puerto Rican, Mexican, and Central and South American). To control for variation among groups, we developed a multi-dimensional clustering method to define a “genetic-analysis group” variable that retains many properties of self-identified background while achieving substantially greater genetic homogeneity within groups and including participants with non-specific self-identification. In GWASs of 22 biomedical traits, we used a linear mixed model (LMM) including pairwise empirical KCs to account for familial relatedness, PCs for ancestry, and genetic-analysis groups for additional group-associated effects. Including the genetic-analysis group as a covariate accounted for significant trait variation in 8 of 22 traits, even after we fit 20 PCs. Additionally, genetic-analysis groups had significant heterogeneity of residual variance for 20 of 22 traits, and modeling this heteroscedasticity within the LMM reduced genomic inflation for 19 traits. Furthermore, fitting an LMM that utilized a genetic-analysis group rather than a self-identified background group achieved higher power to detect previously reported associations. We expect that the methods applied here will be useful in other studies with multiple ethnic groups, admixture, and relatedness.

Background and Purpose— Alcohol consumption is common in the United States and may confer beneficial cardiovascular effects at light-to-moderate doses. The alcohol–stroke relationship remains debated. We estimated the relationship between midlife, self-reported alcohol consumption and ischemic stroke and intracerebral hemorrhage (ICH) in a biracial cohort. Methods— We examined 12 433 never and current drinkers in the Atherosclerosis Risk in Communities study, aged 45 to 64 years at baseline. Participants self-reported usual drinks per week of beer, wine, and liquor at baseline. We used multivariate Cox proportional hazards regression to assess the association of current alcohol consumption relative to lifetime abstention with incident ischemic stroke and ICH and modification by sex–race group. We modeled alcohol intake with quadratic splines to further assess dose–response relationships. Results— One third of participants self-reported abstention, 39% and 24%, respectively, consumed ≤3 and 4 to 17 drinks/wk, and only 5% reported heavier drinking. There were 773 ischemic strokes and 81 ICH over follow-up (median ≈22.6 years). For ischemic stroke, light and moderate alcohol consumption were not associated with incidence (hazard ratios, 0.98; 95% CI, 0.79–1.21; 1.06, 0.84–1.34), whereas heavier drinking was associated with a 31% increased rate relative to abstention (hazard ratios, 1.31; 95% CI, 0.92–1.86). For ICH, moderate-to-heavy (hazard ratios, 1.99; 95% CI, 1.07–3.70), but not light, consumption increased incidence. Conclusions— Self-reported light-to-moderate alcohol consumption at midlife was not associated with reduced stroke risk compared with abstention over 20 years of follow-up in the Atherosclerosis Risk in Communities study. Heavier consumption increased the risk for both outcomes as did moderate intake for ICH.

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value

Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development., Acknowledgements per cohort are listed in Supplementary Note 2. We thank the following studies for sharing their summary level results: QRS voltage (van der Harst et al., 2016)[12], heart rate (den Hoed et al., 2013)[35], RR interval (Eijgelsheim et al., 2010)[11], atrial fibrillation (Christophersen et al., 2017[15]), and CARe-COGENT AA PR Consortium (Butler et al., 2012)[33]. We acknowledge Dr. Vinicius Tragante for his help generating the author list.

While much of the chronic kidney disease (CKD) literature focuses on the role of blood pressure reduction in delaying CKD progression, little is known about the benefits of modest population-wide decrements in blood pressure on incident CKD. The authors used multivariable linear regression to characterize the impact on incident CKD of two approaches for blood pressure management: (1) a 1-mm Hg reduction in systolic BP across the entire study population; and (2) a 10% reduction in participants with unaware, untreated, and uncontrolled BP above goal as defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) thresholds. Over a mean of 20 years of follow-up (ARIC [Atherosclerosis Risk in Communities] study, n = 15 390), 3852 incident CKD events were ascertained. After adjustment, a 1-mm Hg decrement in systolic BP across the population was associated with an estimated 11.7 (95% confidence interval [CI], 6.2-17.3) and 13.4 (95% CI, 10.3-16.6) fewer CKD events per 100 000 person-years in blacks and whites, respectively. Among participants with BP above JNC 7 goal, a 10% decrease in unaware, untreated, or uncontrolled BP was associated with 3.2 (95% CI, 2.0-4.9), 2.8 (95% CI, 1.8-4.3), and 5.8 (95% CI, 3.6-8.8) fewer CKD events per 100 000 person-years in blacks and 3.1 (95% CI, 2.3-4.1), 0.7 (95% CI, 0.5-0.9), and 1.0 (95% CI, 1.3-2.4) fewer CKD events per 100 000 person-years in whites. Modest population-wide reductions in systolic BP hold potential for the primary prevention of CKD.

To examine the ability of total cholesterol (TC), a low-density lipoprotein cholesterol (LDL-C) proxy widely used in public health initiatives, to capture important population-level shifts away from ideal and intermediate LDL-C throughout adulthood. We estimated age (≥20 years)-, race/ethnic (Caucasian, African American, and Hispanic/Latino)-, and sex- specific net transition probabilities between ideal, intermediate, and poor TC and LDL-C using National Health and Nutrition Examination Survey (2007–2014; N = 13,584) and Hispanic Community Health Study/Study of Latinos (2008–2011; N = 15,612) data in 2016 and validated and calibrated novel Markov-type models designed for cross-sectional data. At age 20, >80% of participants had ideal TC, whereas the race/ethnic- and sex-specific prevalence of ideal LDL-C ranged from 39.2%-59.6%. Net transition estimates suggested that the largest one-year net shifts away from ideal and intermediate LDL-C occurred approximately two decades earlier than peak net population shifts away from ideal and intermediate TC. Public health and clinical initiatives focused on monitoring TC in middle-adulthood may miss important shifts away from ideal and intermediate LDL-C, potentially increasing the duration, perhaps by decades, that large segments of the population are exposed to suboptimal LDL-C.

Sulfonylureas, a commonly-used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In eleven ethnically diverse cohorts that included 71 857 European, African American, and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT, and QRS intervals. In ancestry-specific meta-analyses, 8 novel pharmacogenomic loci met the threshold for genome-wide significance (P < 5 x 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

QT interval prolongation is a heritable risk factor for ventricular arrhythmias and can predispose to sudden death. Most genome-wide association studies (GWAS) of QT were performed in European ancestral populations, leaving other groups uncharacterized. Herein we present the first QT GWAS of Hispanic/Latinos using data on 15,997 participants from four studies. Study-specific summary results of the association between 1000 Genomes Project (1000G) imputed SNPs and electrocardiographically measured QT were combined using fixed-effects meta-analysis. We identified 41 genome-wide significant SNPs that mapped to 13 previously identified QT loci. Conditional analyses distinguished six secondary signals at NOS1AP (n = 2), ATP1B1 (n = 2), SCN5A (n = 1), and KCNQ1 (n = 1). Comparison of linkage disequilibrium patterns between the 13 lead SNPs and six secondary signals with previously reported index SNPs in 1000G super populations suggested that the SCN5A and KCNE1 lead SNPs were potentially novel and population-specific. Finally, of the 42 suggestively associated loci, AJAP1 was suggestively associated with QT in a prior East Asian GWAS; in contrast BVES and CAP2 murine knockouts caused cardiac conduction defects. Our results indicate that whereas the same loci influence QT across populations, population-specific variation exists, motivating future trans-ethnic and ancestrally diverse QT GWAS.

Anemia is associated with poor prognosis in patients hospitalized with acute decompensated heart failure (ADHF). Whether the impact of anemia differs by heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF) is uncertain. We examined hospital surveillance data captured by the Atherosclerosis Risk in Communities Study from January 1, 2005, to December 31, 2010. Diagnoses of ADHF were validated by standardized physician review of the medical record. Anemia was classified using the World Health Organization criteria (12 g/dl for women and13 g/dl for men), and HF type was determined by the ejection fraction (40% for HFrEF and ≥40% for HFpEF). Hospital length of stay and 1-year mortality outcomes were analyzed by multivariable regression, weighted to account for the sampling design, and adjusted for demographics and clinical covariates. Over 6 years, 15,461 (weighted) hospitalized events for ADHF (59% HFrEF) occurred in the catchment of the Atherosclerosis Risk in Communities, based on 3,309 sampled events. Anemia was associated with a mortality hazard ratio of 2.1 (95% confidence interval [CI] 1.6 to 2.7) in patients classified with HFpEF and 1.4 (95% CI 1.1 to 1.7) in those with HFrEF; p for interaction = 0.05. The mean increase in length of hospital stay associated with anemia was 3.5 days (95% CI 3.4 to 3.6) for patients with HFpEF, compared with 1.8 days (95% CI 1.7 to 1.9) for those with HFrEF; p for interaction0.0001. In conclusion, the incremental risks of death and lengthened hospital stay associated with anemia are more pronounced in ADHF patients classified with HFpEF than HFrEF.

BACKGROUND Preeclampsia is thought to originate during placentation, with incomplete remodelling and perfusion of the spiral arteries leading to reduced placental vascular capacity. Nitric oxide (NO) and carbon monoxide (CO) are powerful vasodilators that play a role in the placental vascular system. Although family clustering of preeclampsia has been observed, the existing genetic literature is limited by a failure to consider both mother and child. METHODS We conducted a nested case-control study within the Norwegian Mother and Child Birth Cohort of 1545 case-pairs and 995 control-pairs from 2540 validated dyads (2011 complete pairs, 529 missing mother or child genotype). We selected 1518 single-nucleotide polymorphisms (SNPs) with minor allele frequency >5% in NO and CO signalling pathways. We used log-linear Poisson regression models and likelihood ratio tests to assess maternal and child effects. RESULTS One SNP met criteria for a false discovery rate Q-value

Background: It is unclear whether testing for novel risk factors, such as a cardiovascular genetic risk score (cGRS), improves clinical decision making or health outcomes when used for targeting statin initiation in the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Our objective was to estimate the cost-effectiveness of cGRS testing to inform clinical decision making about statin initiation in individuals with low-to-intermediate (2.5%–7.5%) 10-year predicted risk of ASCVD. Methods and Results: We evaluated the cost-effectiveness of testing for a 27-single-nucleotide polymorphism cGRS comparing 4 test/treat strategies: treat all, treat none, test/treat if cGRS is high, and test/treat if cGRS is intermediate or high. We tested a set of clinical scenarios of men and women, aged 45 to 65 years, with 10-year ASCVD risks between 2.5% and 7.5%. Our primary outcome measure was cost per quality-adjusted life-year gained. Under base case assumptions for statin disutility and cost, the preferred strategy is to treat all patients with ASCVD risk >2.5% without cGRS testing. For certain clinical scenarios, such as a 57-year-old man with a 10-year ASCVD risk of 7.5%, cGRS testing can be cost-effective under a limited set of assumptions; for example, when statins cost $15 per month and statin disutility is 0.013 (ie, willing to trade 3 months of life in perfect health to avoid 20 years of statin therapy), the preferred strategy (using a willingness-to-pay threshold of $50 000 per quality-adjusted life-year gained) is to test and treat if cGRS is intermediate or high. Overall, the results were not sensitive to assumptions about statin efficacy and harms. Conclusions: Testing for a 27-single-nucleotide polymorphism cGRS is generally not a cost-effective approach for targeting statin therapy in the primary prevention of ASCVD for low- to intermediate-risk patients.