Background: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the ...European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations. Methods: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inversevariance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test. Results: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity. Conclusions: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.
Antidepressants are often only moderately successful in decreasing the severity of depressive symptoms. In part, antidepressant treatment response in patients with depression is genetically ...determined. However, although a large number of studies have been conducted aiming to identify genetic variants associated with antidepressant drug response in depression, only a few variants have been repeatedly identified. Within the present review, we will discuss the methodological challenges and limitations of the studies that have been conducted on this topic to date (e.g., 'treated-only design', statistical power) and we will discuss how specifically drug-gene interaction models can be used to be better able to identify genetic variants associated with antidepressant drug response in depression.
Despite a lifetime prevalence of at least 5%, developmental stuttering, characterized by prolongations, blocks, and repetitions of speech sounds, remains a largely idiopathic speech disorder. Family, ...twin, and segregation studies overwhelmingly support a strong genetic influence on stuttering risk; however, its complex mode of inheritance combined with thus-far underpowered genetic studies contribute to the challenge of identifying and reproducing genes implicated in developmental stuttering susceptibility. We conducted a trans-ancestry genome-wide association study (GWAS) and meta-analysis of developmental stuttering in two primary datasets: The International Stuttering Project comprising 1,345 clinically ascertained cases from multiple global sites and 6,759 matched population controls from the biobank at Vanderbilt University Medical Center (VUMC), and 785 self-reported stuttering cases and 7,572 controls ascertained from The National Longitudinal Study of Adolescent to Adult Health (Add Health). Meta-analysis of these genome-wide association studies identified a genome-wide significant (GWS) signal for clinically reported developmental stuttering in the general population: a protective variant in the intronic or genic upstream region of SSUH2 (rs113284510, protective allele frequency = 7.49%, Z = −5.576, p = 2.46 × 10−8) that acts as an expression quantitative trait locus (eQTL) in esophagus-muscularis tissue by reducing its gene expression. In addition, we identified 15 loci reaching suggestive significance (p < 5 × 10−6). This foundational population-based genetic study of a common speech disorder reports the findings of a clinically ascertained study of developmental stuttering and highlights the need for further research.
Despite overwhelming evidence in support of strong genetic influence, the genetic etiology of developmental stuttering has remained elusive. This study reveals genome-wide significant and suggestively significant signals for clinically ascertained stuttering cases in the general population, laying essential groundwork for further research into identification of common stuttering susceptibility variants.
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.
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.
Studies examining the health effects of particulate matter <or= 2.5 microm in aerodynamic diameter (PM2.5) commonly use ambient PM2.5 concentrations measured at distal monitoring sites as proxies for ...personal exposure and assume spatial homogeneity of ambient PM2.5. An alternative proxy-the residential outdoor PM2.5 concentration measured adjacent to participant homes-has few advantages under this assumption.
We systematically reviewed the correlation between residential outdoor PM2.5 and personal PM2.5 (-rj) as a means of comparing the magnitude and sources of measurement error associated with their use as exposure surrogates.
We searched seven electronic reference databases for studies of the within-participant residential outdoor-personal PM2.5 correlation.
The search identified 567 candidate studies, nine of which were abstracted in duplicate, that were published between 1996 and 2008. They represented 329 nonsmoking participants 6-93 years of age in eight U.S. cities, among whom -rj was estimated (median, 0.53; range, 0.25-0.79) based on a median of seven residential outdoor-personal PM2.5 pairs per participant. We found modest evidence of publication bias (symmetric funnel plot; pBegg = 0.4; pEgger = 0.2); however, we identified evidence of heterogeneity (Cochran's Q-test p = 0.05). Of the 20 characteristics examined, earlier study midpoints, eastern longitudes, older mean age, higher outdoor temperatures, and lower personal-residential outdoor PM2.5 differences were associated with increased within-participant residential outdoor-personal PM2.5 correlations.
These findings were similar to those from a contemporaneous meta-analysis that examined ambient-personal PM2.5 correlations (rj = median, 0.54; range, 0.09-0.83). Collectively, the meta-analyses suggest that residential outdoor-personal and ambient-personal PM2.5 correlations merit greater consideration when evaluating the potential for bias in studies of PM2.5-mediated health effects.
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.
Most cancer deaths are due to metastases. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells could be helpful to assess patient risk of metastatic disease, even ...among those otherwise diagnosed with local disease. Previous studies of EMT markers and patient outcomes used inconsistent methods and did not compare the clinical impact of different expression cut points for the same marker. Using digital image analysis, we measured the EMT markers Snail and E-cadherin in primary tumor specimens from 190 subjects in tissue microarrays from a population-based prospective cohort of colorectal cancer patients and estimated their associations with time-to-death. After measuring continuous marker expression data, we performed a systematic search for the cut point for each marker with the best model fit between dichotomous marker expression and time-to-death. We also assessed the potential clinical impact of different cut points for the same marker. After dichotomizing expression status at the statistically-optimal cut point, we found that Snail expression was not associated with time-to-death. When measured as a weighted average of tumor cores, low E-cadherin expression was associated with a greater risk of dying within 5 years of surgery than high expression (risk difference = 33 %, 95 % confidence interval 3–62 %). Identifying a clinically-optimal cut point for an EMT marker requires trade-offs between strength and precision of the association with patient outcomes, as well as consideration of the number of patients whose treatments might change based on using the marker at a given cut point.
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