Genome-wide association study of PR interval.
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ABSTRACT:
SUBMITTER: Pfeufer A
PROVIDER: S-EPMC2850197 | biostudies-literature | 2010 Feb
REPOSITORIES: biostudies-literature
Publications
Genome-wide association study of PR interval.
Pfeufer Arne A van Noord Charlotte C Marciante Kristin D KD Arking Dan E DE Larson Martin G MG Smith Albert Vernon AV Tarasov Kirill V KV Müller Martina M Sotoodehnia Nona N Sinner Moritz F MF Verwoert Germaine C GC Li Man M Kao W H Linda WH Köttgen Anna A Coresh Josef J Bis Joshua C JC Psaty Bruce M BM Rice Kenneth K Rotter Jerome I JI Rivadeneira Fernando F Hofman Albert A Kors Jan A JA Stricker Bruno H C BH Uitterlinden André G AG van Duijn Cornelia M CM Beckmann Britt M BM Sauter Wiebke W Gieger Christian C Lubitz Steven A SA Newton-Cheh Christopher C Wang Thomas J TJ Magnani Jared W JW Schnabel Renate B RB Chung Mina K MK Barnard John J Smith Jonathan D JD Van Wagoner David R DR Vasan Ramachandran S RS Aspelund Thor T Eiriksdottir Gudny G Harris Tamara B TB Launer Lenore J LJ Najjar Samer S SS Lakatta Edward E Schlessinger David D Uda Manuela M Abecasis Gonçalo R GR Müller-Myhsok Bertram B Ehret Georg B GB Boerwinkle Eric E Chakravarti Aravinda A Soliman Elsayed Z EZ Lunetta Kathryn L KL Perz Siegfried S Wichmann H-Erich HE Meitinger Thomas T Levy Daniel D Gudnason Vilmundur V Ellinor Patrick T PT Sanna Serena S Kääb Stefan S Witteman Jacqueline C M JC Alonso Alvaro A Benjamin Emelia J EJ Heckbert Susan R SR
Nature genetics 20100110 2
The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two ind ...[more]
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Project description:The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n?=?6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5 x 10??) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta ?=?5.1 msec per minor allele, 95% CI ?=?4.1-6.1, p?=?3 x 10?²³). This SNP was also associated with PR interval (beta?=?2.4 msec per minor allele, 95% CI?=?1.8-3.0, p?=?3 x 10?¹?) in individuals of European ancestry (n?=?14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p?=?0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.
| S-EPMC3037415 | biostudies-literature
Project description:BACKGROUND:The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans. METHODS AND RESULTS:We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ?2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (? range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (?: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)). CONCLUSIONS:This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.
| S-EPMC3560365 | biostudies-literature
Project description: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<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.ConclusionsOur 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.
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Project description: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.
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Project description:QT prolongation is associated with increased risk of cardiac arrhythmias. Identifying the genetic variants that mediate antipsychotic-induced prolongation may help to minimize this risk, which might prevent the removal of efficacious drugs from the market. We performed candidate gene analysis and five drug-specific genome-wide association studies (GWASs) with 492K single-nucleotide polymorphisms to search for genetic variation mediating antipsychotic-induced QT prolongation in 738 schizophrenia patients from the Clinical Antipsychotic Trial of Intervention Effectiveness study. Our candidate gene study suggests the involvement of NOS1AP and NUBPL (P-values=1.45 × 10(-05) and 2.66 × 10(-13), respectively). Furthermore, our top GWAS hit achieving genome-wide significance, defined as a Q-value <0.10 (P-value=1.54 × 10(-7), Q-value=0.07), located in SLC22A23, mediated the effects of quetiapine on prolongation. SLC22A23 belongs to a family of organic ion transporters that shuttle a variety of compounds, including drugs, environmental toxins and endogenous metabolites, across the cell membrane. This gene is expressed in the heart and is integral in mouse heart development. The genes mediating antipsychotic-induced QT prolongation partially overlap with the genes affecting normal QT interval variation. However, some genes may also be unique for drug-induced prolongation. This study demonstrates the potential of GWAS to discover genes and pathways that mediate antipsychotic-induced QT prolongation.
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Project description:Piglet uniformity (PU) and farrowing interval (FI) are important reproductive traits related to production and economic profits in the pig industry. However, the genetic architecture of the longitudinal trends of reproductive traits still remains elusive. Herein, we performed a genome-wide association study (GWAS) to detect potential genetic variation and candidate genes underlying the phenotypic records at different parities for PU and FI in a population of 884 Large White pigs. In total, 12 significant SNPs were detected on SSC1, 3, 4, 9, and 14, which collectively explained 1-1.79% of the phenotypic variance for PU from parity 1 to 4, and 2.58-4.11% for FI at different stages. Of these, seven SNPs were located within 16 QTL regions related to swine reproductive traits. One QTL region was associated with birth body weight (related to PU) and contained the peak SNP MARC0040730, and another was associated with plasma FSH concentration (related to FI) and contained the SNP MARC0031325. Finally, some positional candidate genes for PU and FI were identified because of their roles in prenatal skeletal muscle development, fetal energy substrate, pre-implantation, and the expression of mammary gland epithelium. Identification of novel variants and candidate genes will greatly advance our understanding of the genetic mechanisms of PU and FI, and suggest a specific opportunity for improving marker assisted selection or genomic selection in pigs.
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Project description:QT interval length is an important risk factor for adverse cardiovascular outcomes; however, the genetic architecture of QT interval remains incompletely understood. We conducted a genome-wide association study of 76,995 ancestrally diverse Kaiser Permanente Northern California members enrolled in the Genetic Epidemiology Research on Adult Health and Aging cohort using 448,517 longitudinal QT interval measurements, uncovering 9 novel variants, most replicating in 40,537 individuals in the UK Biobank and Population Architecture using Genomics and Epidemiology studies. A meta-analysis of all 3 cohorts (n = 117,532) uncovered an additional 19 novel variants. Conditional analysis identified 15 additional variants, 3 of which were novel. Little, if any, difference was seen when adjusting for putative QT interval lengthening medications genome-wide. Using multiple measurements in Genetic Epidemiology Research on Adult Health and Aging increased variance explained by 163%, and we show that the ≈6 measurements in Genetic Epidemiology Research on Adult Health and Aging was equivalent to a 2.4× increase in sample size of a design with a single measurement. The array heritability was estimated at ≈17%, approximately half of our estimate of 36% from family correlations. Heritability enrichment was estimated highest and most significant in cardiovascular tissue (enrichment 7.2, 95% CI = 5.7-8.7, P = 2.1e-10), and many of the novel variants included expression quantitative trait loci in heart and other relevant tissues. Comparing our results to other cardiac function traits, it appears that QT interval has a multifactorial genetic etiology.
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Project description:SummaryHere we present INRICH (INterval enRICHment analysis), a pathway-based genome-wide association analysis tool that tests for enriched association signals of predefined gene-sets across independent genomic intervals. INRICH has wide applicability, fast running time and, most importantly, robustness to potential genomic biases and confounding factors. Such factors, including varying gene size and single-nucleotide polymorphism density, linkage disequilibrium within and between genes and overlapping genes with similar annotations, are often not accounted for by existing gene-set enrichment methods. By using a genomic permutation procedure, we generate experiment-wide empirical significance values, corrected for the total number of sets tested, implicitly taking overlap of sets into account. By simulation we confirm a properly controlled type I error rate and reasonable power of INRICH under diverse parameter settings. As a proof of principle, we describe the application of INRICH on the NHGRI GWAS catalog.AvailabilityA standalone C++ program, user manual and datasets can be freely downloaded from: http://atgu.mgh.harvard.edu/inrich/.
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Project description:BackgroundLow cardiorespiratory fitness (V̇O2peak) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve V̇O2peak, there is considerable inter-individual variability in the V̇O2peak response to the same dose of exercise. Understanding how genetic factors contribute to V̇O2peak training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of V̇O2peak response following exercise training.MethodsParticipant change in objectively measured V̇O2peak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated (P < 1 × 10-5) with the magnitude of V̇O2peak response. Findings were tested in an independent validation study (n = 39) and compared to previous research.ResultsNo variants at the genome-wide significance level were found after adjusting for key covariates (baseline V̇O2peak, individual study, principal components which were significantly associated with the trait). A Quantile-Quantile plot indicates there was minor inflation in the study. Twelve novel loci showed a trend of association with V̇O2peak response that reached suggestive significance (P < 1 × 10-5). The strongest association was found near the membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2) gene (rs6959961, P = 2.61 × 10-7). A PPS created from the 12 lead SNPs was unable to predict V̇O2peak response in a tenfold cross validation, or in an independent (n = 39) validation study (P > 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT (P < 1 × 10-4) and the validation study (P < × 10-6), indicating that general effects of the loci exist, and that with a higher statistical power, more significant genetic associations may become apparent.ConclusionsOngoing research and validation of current and previous findings is needed to determine if genetics does play a large role in V̇O2peak response variance, and whether genomic predictors for V̇O2peak response trainability can inform evidence-based clinical practice. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), Trial Id: ACTRN12618000501246, Date Registered: 06/04/2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374601&isReview=true .
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Project description:To increase plumage color uniformity and understand the genetic background of Korean chickens, we performed a genome-wide association study of different plumage color in Korean native chickens. We analyzed 60K SNP chips on 279 chickens with GEMMA methods for GWAS and estimated the genetic heritability for plumage color. The estimated heritability suggests that plumage coloration is a polygenic trait. We found new loci associated with feather pigmentation at the genome-wide level and from the results infer that there are additional genetic effect for plumage color. The results will be used for selecting and breeding chicken for plumage color uniformity.
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