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Background: The 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. Methods: We 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. Results: We identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top SNP in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was with intronic SNP rs3922344 (P = 1.19x10-24) in SCN5A/SCN10A. Three other previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos. Conclusions: Our 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. [ABSTRACT FROM AUTHOR]

Objective: PR 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.Methods: Study-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.Results: We identified a novel genome-wide association (P<5×10-8) with PR at ID2 (rs6730558), which replicated in Asian and European populations (P<0.017). Additionally, we generalised 10 previously identified PR loci to Hispanics/Latinos. Bioinformatics annotation provided evidence for regulatory function in cardiac tissue. Further, for six loci that generalised, the Hispanic/Latino index SNP was genome-wide significant and identical to (or in high linkage disequilibrium with) the previously identified GWAS lead SNP.Conclusions: Our 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. [ABSTRACT FROM AUTHOR]

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 SNPs modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic, 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<5×10−8), we found suggestive evidence (P<5×10−6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (e.g. NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

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.

Background: Activated partial thromboplastin time (aPTT) is a clinical test used to measure the clotting time between the activation of factor XII and the formation of a fibrin clot. Prolonged aPTT indicates a deficiency in the coagulation pathway while shortened aPTT is associated with prothrombotic risk factors and venus thromboembolism. Despite the high heritability of aPTT (40-80%), previous genome-wide association studies (GWAS) of aPTT have been limited to European descent populations, with only a smaller candidate gene study conducted in African Americans. Methods: We included 13,803 participants of European ancestry (EU) and 2,724 participants of African American ancestry (AA) from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium. aPTT, in seconds (s), was measured using standard protocols in plasma with the use of automated coagulometers. Genotype data were imputed to the 1000 Genomes Phase 1 reference panel, and associations were examined using linear regression assuming an additive genetic model and adjusting for global ancestry, age, sex, and study design. Study-specific results were combined using a fixed-effects, inverse variance weighted meta-analysis. Results: We identified seven loci associated with aPTT in EU populations (F5, FRMD5, KNG1, F11, F12, HLA, ABO) and three loci associated with aPTT in AA populations (KNG1, F12, ABO) at genome-wide significant levels (P < 5x10-8). These results are consistent with previously reported genetic studies in EU and AA populations. Effect sizes were larger in AA populations (1.08 to 1.32 s) than in EU populations (0.40 to 1.00 s). Conclusions: We successfully replicated associations with aPTT at seven loci in EU populations and three loci in AA populations. Our results suggest that genetic determinants of aPTT are consistent across race/ethnicity but that studies in AA populations are currently underpowered relative to EU populations. Future work in aPTT genetics should consider more diverse populations. [ABSTRACT FROM AUTHOR]

PR interval (PR) prolongation is a predictor of atrial fibrillation, a common cardiac arrhythmia, and is an established risk factor for pacemaker implantation, heart failure, stroke, and all-cause mortality. Previous genome-wide association studies in European (EU) and African (AA) descent populations have identified multiple loci associated with PR. However, it is unclear whether these loci are relevant in other racial groups, including Hispanic/Latinos (HL). Extending studies to include admixed populations such as HL also provides the potential to narrow regions associated with PR and identify population specific variants. Therefore, we evaluated 1,135 SNPs from four previously identified PR loci (SCN5A, SCN10A, CAV1-CAV2, and TBX5-TBX3), fine-mapped on the Illumina Metabochip for association with PR. Associations were examined using linear regression assuming an additive genetic model and adjusting for global ancestry and clinical covariates (age, sex, RR interval, body mass index, height, systolic blood pressure) in 11,800 HL participants from participating studies of the Population Architecture using Genomics and Epidemiology (PAGE) consortia. Three of the four loci (SCN5A, SCN10A, and CAV1-CAV2) generalized to HL populations (P<7.1E-4 based on the number of SNPs correlated at r²>0.2 with EU-identified index SNPs). At each of these loci, we identified SNPs with stronger evidence of association with PR than the EU-identified index SNP when examined in the HL population (SCN5A: rs7374540; SCN10A: rs6801957; CAV-CAV2: rs717957). Conditional analyses also identified two additional independent SNPs at each of the three generalized loci (SCN5A: rs3796387, rs9861242; SCN10A: rs10428132, rs7433723; CAV1-CAV2: rs3801995, rs3807994), representing potential secondary signals. Furthermore, linkage disequilibrium (LD) patterns in Hispanics enabled the narrowing of the regions flanking the EU-identified index SNPs. For example, at the CAV1-CAV2 locus, HL LD patterns indicated that seven SNPs were in LD with rs3807989, the EU-identified index SNP, compared to 17 SNPs that were in LD with rs3807989 when applying EU LD patterns, reducing the size of the region by 71 kilobases. Finally, we examined evidence for population specific signals outside of the specific regions identified in EU populations which were associated with PR in Hispanics by focusing on SNPs uncorrelated with the EU index signals. At all four loci, multiple SNPs had evidence of association independent of the signals examined based on EU results. In conclusion, the same genetic loci that influence PR in European descent populations are also important in Hispanic populations, although we detected evidence for population specific SNPs. These results emphasize the importance of examining genetic associations in diverse populations in order to narrow the genomic interval for future functional interrogation. [ABSTRACT FROM AUTHOR]