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Search Results for all work with filters:

  • Alonso, Alvaro
  • Health Sciences, Epidemiology
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Work 1-8 of 8

Sorted by relevance

Article

Whole Exome Sequencing in Atrial Fibrillation.

by Steven A. Lubitz; Jennifer A. Brody; Nathan A. Bihlmeyer; Carolina Roselli; Lu-Chen Weng; Ingrid E. Christophersen; Alvaro Alonso; Eric Boerwinkle; Richard A. Gibbs; Joshua C. Bis; NHLBI GO Exome Sequencing Project; L. Adrienne Cupples; Peter J. Mohler; Deborah A. Nickerson; Donna Muzny; Marco V. Perez; Bruce M. Psaty; Elsayed Z. Soliman; Nona Sotoodehnia; Kathryn L. Lunetta; Emelia J. Benjamin; Susan R. Heckbert; Dan E. Arking; Patrick T. Ellinor; Honghuang Lin

2016

Subjects
  • Biology, Genetics
  • Health Sciences, Epidemiology
  • File Download
  • View Abstract

Abstract:Close

Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.

Article

Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans

by Daniel S. Evans; Christy L. Avery; Mike A. Nalls; Guo Li; John Barnard; Erin N. Smith; Toshiko Tanaka; Anne M. Butler; Sarah G. Buxbaum; Alvaro Alonso; Dan E. Arking; Gerald S. Berenson ; Joshua C. Bis; Steven Buyske; Cara L. Carly; Wei Chen; Mina K. Chung; Steven R. Cummings; Rajat Deo; Charles B. Eaton; Ervin R. Fox; Susan R. Heckbert; Gerardo Heiss; Lucia A. Hindorff; Wen-Chi Hsueh; Aaron Isaacs; Yalda Jamshidi; Kathleen F. Kerr ; Felix Liu; Yongmei Liu; Kurt K. Lohman; Jared W. Magnani; Joseph F. Maher ; Reena Mehra; Yan A. Meng; Solomon K. Musani; Christopher Newton-Cheh; Kari E. North; Bruce M. Psaty; Susan Redline; Jerome I. Rotter; Renate B. Schnabel; Nicholas J. Schork; Ralph V. Schohet; Andrew B. Singleton; Jonathan D. Smith ; Elsayed Z. Soliman; Sathanur R. Srinivasan; Herman A. Taylor, Jr.; David R. Van Wagoner; James G. Wilson ; Taylor Young ; Zhu-MIng Zhang; Alan B. Zonderman; Michelle K. Evans; Luigi Ferucci; Sarah S. Murray; Gregory J. Tranah; Eric A. Whitsel; Alex P. Reiner; Nona Sotoodehnia

2016

Subjects
  • Biology, Genetics
  • Health Sciences, Epidemiology
  • Health Sciences, Public Health
  • File Download
  • View Abstract

Abstract:Close

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10-14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10-4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10-9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10-7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

Article

Association of sickle cell trait with measures of cognitive function and dementia in African Americans

by Nemin Chen; Christina Caruso; Alvaro Alonso; Vimal K. Derebail; Abhijit V. Kshirsagar; A. Richey Sharrett; Nigel S. Key; Rebecca F. Gottesman; Megan L. Grove; Jan Bressler; Eric Boerwinkle; B. Gwen Windham; Thomas H. Mosley, Jr.; Hyacinth Idu Hyacinth

2019

Subjects
  • Biology, Neuroscience
  • Biology, Genetics
  • Health Sciences, Epidemiology
  • File Download
  • View Abstract

Abstract:Close

Objective: The incidence and prevalence of cognitive decline and dementia are significantly higher among African Americans compared with non-Hispanic Whites. The aim of this study was to determine whether inheritance of the sickle cell trait (SCT) i.e. heterozygosity for the sickle cell mutation increases the risk of cognitive decline or dementia Among African Americans. Methods: We studied African American participants enrolled in the Atherosclerosis Risk in Communities study. SCT genotype at baseline and outcome data from cognitive assessments at visits 2, 4 and 5, and an MRI performed at visit 5 were analyzed for the association between SCT and risk of cognitive impairment and/or dementia. Results: There was no significant difference in risk factors profile between participants with SCT (N = 176) and those without SCT (N = 2532). SCT was not independently associated with a higher prevalence of global or domain-specific cognitive impairment at baseline or with more rapid cognitive decline. Participants with SCT had slightly lower incidence of dementia (HR = 0.63 [0.38, 1.05]). On the other hand, SCT seems to interact with the apolipoprotein E ε4 risk allele resulting in poor performance on digit symbol substitution test at baseline (z-score = −0.08, Pinteraction = 0.05) and over time (z-score = −0.12, Pinteraction = 0.04); and with diabetes mellitus leading to a moderately increased risk of dementia (HR = 2.06 [0.89, 4.78], Pinteraction = 0.01). Conclusions: SCT was not an independent risk factor for prevalence or incidence of cognitive decline or dementia, although it may interact with and modify other putative risk factors for cognitive decline and dementia.

Article

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

by Ionna Ntalla; Lu-Chen Weng; James H. Cartwright; Amelia Weber Hall; Gardar Sveinbjornsson; Nathan R. Tucker; Seung Hoan Choi; Adolfo Correa; Alvaro Alonso; Steven A. Lubitz

2020

Subjects
  • Biology, Genetics
  • Health Sciences, Epidemiology
  • Health Sciences, Oncology
  • Health Sciences, Public Health
  • File Download
  • View Abstract

Abstract:Close

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.

Article

NT-proBNP as a mediator of the racial difference in incident atrial fibrillation and heart failure

by Isaac R. Whitman; Eric Vittinghoff; Christopher R. DeFilippi; John S. Gottdiener; Alvaro Alonso; Bruce M. Psaty; Susan R. Heckbert; Ron C. Hoogeveen; Dan E. Arking; Elizabeth Selvin; Lin Y. Chen; Thomas A. Dewland; Gregory M. Marcus

2019

Subjects
  • Health Sciences, Epidemiology
  • Health Sciences, Medicine and Surgery
  • Biology, Genetics
  • File Download
  • View Abstract

Abstract:Close

Background-Blacks harbor more cardiovascular risk factors than whites, but experience less atrial fibrillation (AF). Conversely, whites may have a lower risk of heart failure (CHF). N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels are higher in whites, predict incident AF, and have diuretic effects in the setting of increased ventricular diastolic pressures, potentially providing a unifying explanation for these racial differences. Methods and Results-We used data from the CHS (Cardiovascular Health Study) to determine the degree to which baseline NTproBNP levels mediate the relationships between race and incident AF and CHF by comparing beta estimates between models with and without NT-proBNP. The ARIC (Atherosclerosis Risk in Communities) study was used to assess reproducibility. Among 4731 CHS (770 black) and 12 418 ARIC (3091 black) participants, there were 1277 and 1253 incident AF events, respectively. Whites had higher baseline NT-proBNP (CHS: 40% higher than blacks; 95% CI, 29-53; ARIC: 39% higher; 95% CI, 33-46) and had a greater risk of incident AF compared with blacks (CHS: adjusted hazard ratio, 1.60; 95% CI, 1.31-1.93; ARIC: hazard ratio, 1.93; 95% CI, 1.57-2.27). NT-proBNP levels explained a significant proportion of the racial difference in AF risk (CHS: 36.2%; 95% CI, 23.2- 69.2%; ARIC: 24.6%; 95% CI, 14.8-39.6%). Contrary to our hypothesis, given an increased risk of CHF among whites in CHS (adjusted hazard ratio, 1.20; 95% CI, 1.05-1.47) and the absence of a significant association between race and CHF in ARIC (adjusted hazard ratio, 1.07; 95% CI, 0.94-1.23), CHF-related mediation analyses were not performed. Conclusions-A substantial portion of the relationship between race and AF was statistically explained by baseline NT-proBNP levels. No consistent relationship between race and CHF was observed.

Article

Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

by Seung Hoan Choi; Lu-Chen Weng; Carolina Roselli; Honghuang Lin; Christopher M. Haggerty; M. Benjamin Shoemaker; John Barnard; Dan E. Arking; Daniel I. Chasman; Christine M. Albert; Mark Chaffin; Nathan R. Tucker; Jonathan D. Smith; Namrata Gupta; Stacey Gabriel; Lauren Margolin; Marisa A. Shea; Christian M. Shaffer; Zachary T. Yoneda; Eric Boerwinkle; Alvaro Alonso

2018

Subjects
  • Health Sciences, Medicine and Surgery
  • Health Sciences, Epidemiology
  • Biology, Genetics
  • File Download
  • View Abstract

Abstract:Close

Importance: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. Objective: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346546 participants) and the MyCode Study (42782 participants). Exposures: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. Main Outcomes and Measures: Early-onset AF (defined as AF onset in persons <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10 -3 . Results: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10 -4 ), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10 -5 ). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P =.01). Conclusions and Relevance: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.

Article

Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits

by Jessica van Setten; Niek Verweij; Hamdi Mbarek; Maartje N. Niemeijer; Stella Trompet; Dan E. Arking; Jennifer A. Brody; Ilaria Gandin; Niels Grarup; Leanne M. Hall; Daiane Hemerich; Leo-Pekka Lyytikainen; Hao Mei; Martina Mueller-Nurasyid; Bram P. Prins; Antonietta Robino; Albert V. Smith; Helen R. Warren; Folkert W. Asselbergs; Alvaro Alonso

2019

Subjects
  • Health Sciences, Medicine and Surgery
  • Health Sciences, Epidemiology
  • Biology, Genetics
  • File Download
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Abstract:Close

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.

Article

Mitochondrial DNA copy number and incident atrial fibrillation

by Di Zhao; Traci M. Bartz; Nona Sotoodehnia; Wendy S. Post; Susan R. Heckbert; Alvaro Alonso; Ryan J. Longchamps; Christina A. Castellani; Yun Soo Hong; Jerome I. Rotter; Henry J. Lin; Brian O'Rourke; Nathan Pankratz; John A. Lane; Stephanie Y. Yang; Eliseo Guallar; Dan E. Arking

2020

Subjects
  • Biology, Genetics
  • Health Sciences, Epidemiology
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Abstract:Close

Background: Mechanistic studies suggest that mitochondria DNA (mtDNA) dysfunction may be associated with increased risk of atrial fibrillation (AF). The association between mtDNA copy number (mtDNA-CN) and incident AF in the general population, however, remains unknown. Methods: We conducted prospective analyses of 19,709 participants from the Atherosclerosis Risk in Communities Study (ARIC), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Cardiovascular Health Study (CHS). mtDNA-CN from the peripheral blood was calculated from probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms (SNP) Array 6.0 in ARIC and MESA and from multiplexed real-time quantitative polymerase chain reaction (qPCR) in CHS. Incident AF cases were identified through electrocardiograms, review of hospital discharge codes, Medicare claims, and death certificates. Results: The median follow-up time was 21.4 years in ARIC, 12.9 years in MESA, and 11.0 years in CHS, during which 4021 participants developed incident atrial fibrillation (1761 in ARIC, 790 in MESA, and 1470 in CHS). In fully adjusted models, participants with the lowest quintile of mitochondria DNA copy number had an overall 13% increased risk (95% CI 1 to 27%) of incident atrial fibrillation compared to those with the highest quintile. Dose-response spline analysis also showed an inverse association between mitochondria DNA copy number and hazard for atrial fibrillation for all three cohorts. These associations were consistent across subgroups. Conclusions: Mitochondria DNA copy number was inversely associated with the risk of AF independent of traditional cardiovascular risk factors. These findings implicate mitochondria DNA copy number as a novel risk factor for atrial fibrillation. Further research is warranted to understand the underlying mechanisms and to evaluate the role of mitochondria DNA copy number in the management of atrial fibrillation risk.
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