Linkage Analysis in AF
It is well-documented that AF is a highly heritable20,21 condition. A study using monozygotic twins revealed a heritability estimate of 62%22, while population based estimates using common genetic variants in a European cohort indicated 22.1% heritability among patients with AF, irrespective of age at AF onset and sex.23 Given this, multiple inquiries into the genetic basis of AF have been developed and have focused on a variety of analytic techniques, including gene linkage among families with autosomal dominant AF, genome-wide association studies (GWAS), and single gene variant analyses, which highlight the complex contribution of genetics to AF development (Figure 1 ).17 Multiple rare single gene gain-of-function (GOF) and loss-of-function (LOF) variants in genes encoding ion channels relevant to the cardiac conduction cycle, transcription factors,24 and structural proteins, including those involved in the myocardial sarcomere25-27, have been identified in linkage studies which identify recombination events between genetic markers and trait loci in generally large, multi-generational families. One such gene, KCNQ1 , encodes a portion of the Iks channel involved in cardiac myocyte repolarization and is associated with long QT syndrome type 1; GOF mutations in this gene have also been associated with early onset AF, a normal correct QT interval, and left ventricular dilation.28