NHLBI TOPMed - NHGRI CCDG: The Johns Hopkins University School of Medicine Atrial Fibrillation Genetics Study


The description below was taken directly from the NCBI database of Genotypes and Phenotypes (dbGaP):

This study is part of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Program. TOPMed is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment. TOPMed will contribute to this initiative through the integration of whole-genome sequencing (WGS) and other -omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program aims to uncover factors that increase or decrease the risk of disease, to identify subtypes of disease, and to develop more targeted and personalized treatments. Two genotype call sets derived from WGS are now available, Freeze 5b (GRCh38) and Freeze 8 (GRCh38), with largely overlapping sample sets. Information about how to identify other TOPMed WGS accessions for cross-study analysis, as well as descriptions of TOPMed methods of data acquisition, data processing and quality control, are provided in the accompanying documents, "TOPMed Whole Genome Sequencing Project - Freeze 5b, Phases 1 and 2" and "TOPMed Whole Genome Sequencing Project - Freeze 8, Phases 1-4". Please check the study list at the top of each of these methods documents to determine whether it applies to this study accession.

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is the primary cause of many hospital admissions, and is associated with significant secondary morbidity by increasing the risk of stroke, heart failure, and all-cause mortality. The incidence of AF is on the rise, and it is projected that by the year 2050 more than 10 million patients will be affected by AF in the United States alone. Anti-arrhythmic medications have limited success in maintaining sinus rhythm, are associated with side effects, and appear ineffective at reducing mortality compared to a strategy of rate control and anticoagulation. Given the significant morbidity associated with this common arrhythmia, surgical and catheter ablation techniques have been developed to treat AF. However, despite the incorporation of various strategies for ablation, long-term recurrence rates of AF remain higher than 25 percent after ablation. Current techniques for catheter ablation of AF include pulmonary vein isolation and complex fractionated atrial electrogram (CFAE) ablation. However, the contribution of each strategy to long-term procedural success and the relative importance of each strategy for different patients remain unknown. Recent advances in cardiac imaging have allowed detailed analysis of left atrial myocardial anatomy. Parallel advances in molecular genetics have identified several candidate genes involved in familial and non-familial AF. However, the pathophysiology of AF generation and maintenance, and the potential contribution of such genetic or anatomic substrates for patient selection, and for target identification during catheter ablation have not yet been examined. Advances in molecular genetics and imaging, coupled with techniques for endocardial and epicardial mapping in the electrophysiology laboratory present an opportunity to significantly improve our understanding of (1) The relation of paroxysmal versus persistent AF with (a) structural left atrial changes (left/right atrial scar, wall thinning, pulmonary vein anomalies, and coronary sinus dilation) and with (b) candidate genetic variants. (2) The relation of candidate genetic variants with (a) structural left atrial changes and with (b) electrophysiologic properties (atrial effective refractory period (AERP) inhomogeneity, voltage abnormalities, trigger burden and location, C FAE extent and location), (3) The relation of structural left atrial changes with (a) CFAE location as targets for catheter ablation and with (b) reversible conduction block/myocardial injury after pulmonary vein isolation, and (4) Individualized endocardial targets for AF ablation based on candidate genes and anatomic substrates. The proposed study will improve our understanding of the underlying pathophysiology of AF, and may improve current techniques for treatment of this important arrhythmia.

General information

phs#Study abbreviationStudy typeParent phs#
phs001598JHU_AFCase setN/A