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Massive Atrial Fibrillation GWAS Leads to 80 New Risk Loci

NEW YORK (GenomeWeb) – A genome-wide association study involving more than a million people has linked 111 loci to atrial fibrillation risk — 80 of which are new — and has helped to focus in on functional candidate genes behind the common cardiac arrhythmia.

By bringing together data from half a dozen genetic large studies or databases, investigators from the University of Michigan, the Norwegian University of Science and Technology, and elsewhere compared variant profiles from 1,030,836 individuals with or without atrial fibrillation. Using array- and/or sequence-based data generated for the Decode, Michigan Genomics Initiative, UK Biobank, Nord-Trondelag Health Study, DiscovEHR, and AFGen Consortium projects, the team searched for ties between atrial fibrillation and some 34.7 million variants in 60,620 individuals affected by the cardiac arrhythmia and 970,216 unaffected controls.

The analysis, published online today in Nature Genetics, revealed 142 variants with genome-wide significant ties to atrial fibrillation, falling at 80 new loci and 31 of the 35 loci previously implicated in the condition.

Through a series of follow-up analyses — hinging on available cell type expression, epigenetic profiles, and predicted protein-altering effects of atrial fibrillation-associated variants — the team focused in on 151 candidate genes suspected of having a functional role in the condition, including genes previously implicated in cardiac or skeletal muscle function, cardiomyopathy, and/or heart development. The group also saw signs that atrial fibrillation may involve genes contributing to everything from structural remodeling of the heart's muscle tissue (called the myocardium) to heart-related signaling and regulatory processes.

"We highlighted genes important for function of cardiac ion channels and calcium signaling, along with cardiac transcription factors, which in turn could also affect the electrical properties of the myocardium," the authors wrote, "and in addition prioritized multiple atrial fibrillation functional candidate genes likely to be involved in structural integrity and function of heart and skeletal muscle."

From there, the investigators went on to explore potential drug targets in this set, along with roles for two of these genes — MYH6 and MYH7 — in a rabbit model of atrial fibrillation. They also came up with a proposed polygenic risk score for the disease, which appeared to coincide with the risk of other heart-related diseases in individuals from the UK Biobank project.

The authors concluded that the new results "need confirmation but provide a foundation for directing future functional experiments to better understand the biology underlying atrial fibrillation."