Genome-Wide Association Studies Revealing the Heritability of Common Atrial Fibrillation: Is Bigger Always Better?

In this issue of Circulation Cardiovascular Genetics, Weng et al1 present an interesting study evaluating the heritability of atrial fibrillation (AF). See Article by Weng et al AF is the most common arrhythmia worldwide, and substantial efforts have been made to elucidate mechanisms underlying its onset and progression.2 Over the past years, a growing body of evidence demonstrated that AF is heritable. Besides rare genetic mutations with strong effects and a clear phenotype, such as gain- or loss-of-function mutations in ion channel genes,3–5 there are common genetic variants or single nucleotide polymorphisms that have been shown to be associated with AF although a causal mechanistic role has not been identified for most of the risk variants.6–11 Several studies tried to evaluate the degree of heritability by family-based or population-based studies, such as the Danish twin study that reported an AF heritability of 62% or the Framingham Heart Study that showed a 40% risk to develop AF if a first-degree relative is affected.12,13 Those numbers raised some concerns because studies performed in families might not adequately mirror the situation in the general population and might hence overestimate the true heritability. Also, it is in contrast to the experience from daily clinical practice where AF is predominantly seen in older patients with comorbidities, that is, in patients with several likely causes for AF, making a genetic cause of the disease less likely. It, therefore, remained unclear to which degree AF can be …