Understanding the genetic basis of atrial fibrillation : next steps after genome-wide association studies

Abstract

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in clinical practice. Over the past two decades, we have come to appreciate that AF has a significant heritable component. The recent advent of next-generation sequencing technology has spawned a new era of research into the genetic basis of AF. Genome-wide association studies (GWAS) have identified multiple common variants underlying AF. Further, exome sequencing has emerged as a potentially powerful technique for the identification of mutations underlying familial forms of AF. In this thesis, we sought to further elucidate the genetic basis of AF though two specific aims. Firstly, we investigated the mechanistic link between KCNN3, a potassium channel gene which was identified in a GWAS for lone AF, and arrhythmia pathogenesis. Secondly, we performed exome sequencing and classical linkage analysis in two AF pedigrees to identify novel mutations for the arrhythmia. We demonstrate that overexpression of Kcnn3 in a murine model results in an increased susceptibility to AF. Interestingly, these mice also display a high incidence of sudden death due to heart block. Exome sequencing in an AF pedigree identified a potentially causative mutation in the transcription factor gene GATA6. In a second AF pedigree, we identified a novel locus for the arrhythmia on chromosome 1. However the causative mutation at this locus remains elusive. Ultimately, the identification of the genetic substrate underlying AF is likely to uncover novel therapeutic targets as well as enhancing risk stratification for this common and morbid arrhythmia