We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. Using the UK Biobank, we performed a phenome-wide association study (pheWAS) for 12 AF risk factors. Distinct clusters of variants were associated with AF as well as height, BMI, and hypertension. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
Understanding the Genetic Basis of Cardiac Arrhythmias
Cardiac arrhythmias are leading causes of morbidity and sudden death, however the pathophysiologic basis of arrhythmias largely remains unclear. In recent years, heritability of arrhythmias has been described suggesting a genetic basis. We specifically intend to identify the genetic causes of cardiac arrhythmias, assess the causal relations between cardiac arrhythmias and long-term morbidity, estimate the long-term risks of genetic predisposition to cardiac arrhythmias, and determine the relations between cardiac arrhythmias and other cardiovascular traits including cardiac conduction, cardiac structural features, and myocardial related biomarkers. Cardiac arrhythmias are a common source of morbidity, yet the mechanisms are poorly understood. Our proposal is designed to address the genetic underpinnings of cardiac arrhythmias, and assess their relations with morbidity. Our proposal has the potential to provide novel insights into the pathophysiological and biological mechanisms of cardiac arrhythmias. We believe that our findings may yield novel preventative, diagnostic, and therapeutic insights. We submit that our proposal is consistent with the UK Biobank's goal of improving the understanding of common diseases and improving public health. We will examine the genetic underpinnings of common cardiac arrhythmias, including tachyarrhythmias (disorders involving fast heart rates, such as supraventricular tachycardias), and bradyarrhythmias (disorders involving slow heart rates, such as those necessitating pacemaker implantation). Phenotypes will be ascertained on the basis of diagnostic codes (ICD), procedure codes and operations, and self-report. The research will involve both common and rare variant genetic association testing across the genome with cardiac arrhythmia phenotypes. The results of analyses will be meta-analyzed with other independent analyses to enhance power. We will use contemporary statistical approaches and significance thresholds for determining significance. We anticipate using the full cohort for this proposal.
|Lead investigator:||Dr Steven Lubitz|
|Lead institution:||Broad Institute|
4 related Returns
|Return ID||App ID||Description||Archive Date|
|2686||17488||Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation||30 Oct 2020|
|2687||17488||Frequency of Cardiac Rhythm Abnormalities in a Half Million Adults||30 Oct 2020|
|2689||17488||Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation||30 Oct 2020|
|2685||17488||Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery||30 Oct 2020|
|2689||Multi-Ethnic Genome-wide Association Study for Atrial Fibrillation||Roselli et al||2018||Nature Genetics (2018)|