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