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\begin{document}

\title{Genetically Based Atrial Fibrillation: Current Considerations for
Diagnosis and Management}



\author[1]{Anthony V. Pensa}%
\author[2]{Jayson R. Baman}%
\author[3]{Megan J. Puckelwartz}%
\author[2]{Jane Wilcox}%
\affil[1]{Northwestern University Department of Medicine}%
\affil[2]{Northwestern University Division of Cardiology}%
\affil[3]{Northwestern University Feinberg School of Medicine Department of Pharmacology}%


\vspace{-1em}



  
  \date{June 13, 2024}


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\selectlanguage{english}
\begin{abstract}
Atrial fibrillation (AF) is the most common atrial arrhythmia and is
subcategorized into numerous clinical phenotypes. Given its
heterogeneity, investigations into the genetic mechanisms underlying AF
have been pursued in recent decades, with predominant analyses focusing
on early onset or lone AF. Linkage analyses, genome wide association
studies (GWAS), and single gene analyses have led to the identification
of rare and common genetic variants associated with AF risk. Significant
overlap with genetic variants implicated in dilated cardiomyopathy
syndromes, including truncating variants of the sarcomere protein titin,
have been identified through these analyses, in addition to other genes
associated with cardiac structure and function. Despite this, widespread
utilization of genetic testing in AF remains hindered by the unclear
impact of genetic risk identification on clinical outcomes and the high
prevalence of variants of unknown significance (VUS). However, genetic
testing is a reasonable option for patients with early onset AF and in
those with significant family history of arrhythmia. While many
knowledge gaps remain, emerging data support genotyping to inform
selection of AF therapeutics. In this review we highlight the current
understanding of the complex genetic basis of AF and explore the overlap
of AF with inherited cardiomyopathy syndromes. We propose a set of
criteria for clinical genetic testing in AF patients and outline future
steps for the integration of genetics into AF care.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Atrial fibrillation (AF) is the most common atrial arrhythmia and
confers increased risk of cardiovascular morbidity and mortality. AF
carries a significantly increased risk of incident and recurrent
ischemic stroke\textsuperscript{1,2}, myocardial infarction, heart
failure\textsuperscript{3}, and all-cause
mortality.\textsuperscript{4}In addition, AF directly impacts patient
outcomes and quality of life, and, over the past few decades, multiple
randomized trials have been aimed at evaluating the effects of various
antiarrhythmic drugs (AAD) and procedural interventions to affect these
outcomes.\textsuperscript{5-10} However, there is significant
heterogeneity in the clinical phenotype of, as well as management
strategies for, AF.\textsuperscript{11-13} Given the rising
prevalence\textsuperscript{14} of and significant public health burden
incurred by AF and its associated heterogeneity, recent work has focused
on the genetic underpinnings of AF and its implications on diagnosis and
treatment-specific outcomes.\textsuperscript{15}

Genetic analysis has largely been focused on the clinical subgroup of
`early onset AF' or `lone AF,' typically defined as clinically
recognized AF in a patient \textless{}66 years old and in the absence of
structural heart disease.\textsuperscript{16} This work has resulted in
the identification of multiple genes in familial forms of AF and single
nucleotide polymorphisms (SNPs) associated with the development of this
clinical sub-phenotype of AF\textsuperscript{17,18}; additionally, many
of the same genetic loci have been identified as modulators of clinical
response to AF therapeutics. Despite these advances, contemporary
guidelines do not support the routine use of genetic testing in AF
patients.\textsuperscript{19} Herein, we describe the current
understanding of the association between genetic susceptibility and AF,
review challenges related to patient selection for genetic testing, and
describe the outcomes of AAD and catheter interventions for genetically
mediated AF. Further, we propose potential next steps in the
understanding and integration of genetics into clinical AF care.

\textbf{GENETIC BASIS OF AF}

Linkage Analysis in AF

It is well-documented that AF is a highly
heritable\textsuperscript{20,21} condition. A study using monozygotic
twins revealed a heritability estimate of 62\%\textsuperscript{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.\textsuperscript{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 (\textbf{Figure 1}
).\textsuperscript{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,\textsuperscript{24} and structural proteins, including those
involved in the myocardial sarcomere\textsuperscript{25-27}, 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, \emph{KCNQ1} , encodes a
portion of the I\textsubscript{ks} 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.\textsuperscript{28}

AF Genome Wide Association Analysis

Notably, the identification of mutations derived from linkage analyses
is relatively uncommon, and most often found in patients with
early-onset lone AF (\textless{}40-45 years of age at AF onset) and have
a relatively small impact on population-level
AF.\textsuperscript{29,30}To interrogate more common variants that
contribute to AF, GWAS studies compare patients with AF and unaffected
controls and have identified SNPs that associate with increased risk of
AF development. To date, over 100 loci have been identified to have
genome-wide significance in AF risk, the majority of which have been
studied in large populations of patients predominantly of European
ancestry. Large cohort studies have revealed that European ancestry
subjects have an increased risk of AF when compared to African, Asian,
and Hispanic ancestry subjects, which suggests that these populations
have different risk alleles or that the frequency of risk alleles
differs significantly between groups.\textsuperscript{31-34} The largest
multi-ethnic meta-analysis of GWAS for AF to-date had 84\% European
ancestry and identified 97 loci associated with AF, including 67 that
were novel in a combined ancestry analysis and 3 that were
European-specific.\textsuperscript{29} The region that was most
significantly associated with AF across ancestries was 4q25, upstream of
the \emph{PITX2} gene. Effect estimates were similar for the top
associations, suggesting that genetic susceptibility for AF is
relatively constant across ancestries. However, this meta-analysis with
more than half a million participants only included 43,000 non-European
subjects, with Asian ancestry most represented and Hispanic the least.
Asian ancestry-specific GWAS have replicated some of these loci
including \emph{PITX2} , \emph{TBX5} (which is associated with
fibroblast differentiation)\textsuperscript{35} and \emph{ZFHX3} (a zinc
finger-encoding gene associated with cellular differentiation located at
16q22), were found to be associated with early onset
AF.\textsuperscript{36,37} However, in a small Hispanic/Latino cohort,
of the 9 AF risk SNPs examined, only \emph{PITX2} replicated,
highlighting the complex heterogeneity in AF
genetics.\textsuperscript{38} There is a pressing need to improve
diversity in studies of AF. Many loci are similar across ancestries, but
prevalence and outcomes differ suggesting that shared loci may provide
general disease mechanisms and unique loci may modify disease based on
diverse genetic backgrounds or environmental effects. Efforts are
underway to improve diversity in genetic studies including expansion of
biobanks in China and Africa. In the US, programs such as the National
Heart, Lung, and Blood Institute's TOPMed Program, the Million Veteran
Program, and the All of Us Research Program are trying to address these
disparities in genetic studies.

Despite this, GWAS analyses have identified multiple genes associated
with increased AF risk that are implicated in various aspects of cardiac
myocyte function. SNPs located in genes encoding ion channels,
including\emph{KCNQ1} \textsuperscript{39,40}, and the angiotensinogen
gene (\emph{AGT} )\textsuperscript{411} have been associated with
increased risk of AF. Additionally, the 4q25 locus has consistently been
strongly associated with AF risk in all-comers\textsuperscript{42}, lone
AF\textsuperscript{43}, and new AF after coronary artery bypass
surgery.\textsuperscript{44} The 4q25 locus is an inter-codon region
near the gene for transcription factor \emph{PITX2} . This gene is known
to regulate right-left differentiation in embryonic cardiac
development.\textsuperscript{45} Additionally,
\emph{PITX2}overexpression leads to modification of L-type calcium and
delayed rectifier potassium current, resulting in increased AF
susceptibility through multiple pathways.\textsuperscript{46} Presence
of multiple alleles in 4q25 is associated with a risk gradient for AF
development\textsuperscript{47} and has been demonstrated to increase
the likelihood of AF development in family members with rare genetic
AF-associated variants.\textsuperscript{48} This suggests that other
identified AF-associated SNPs may modulate AF development in those with
rare, AF-associated mutations.

Single Gene Analyses, TTN Cardiomyopathy, and Polygenic Risk

The variety of mutations and SNPs identified in familial AF and by GWAS
has led to comparative analyses of single genes and SNPs between AF and
controls. In patients with early-onset AF, approximately 10\% have an
identifiable variant that is associated with either an inherited
arrhythmia or cardiomyopathy syndrome, with the odds of carrying a
disease-associated variant increasing by 25\% per decade at earlier time
of AF diagnosis.\textsuperscript{49} One such gene that has garnered
significant attention is \emph{SCN5A} , which encodes the sodium channel
that controls inward sodium current as part of atrial
depolarization.\textsuperscript{50} \emph{SCN5A} mutations have been
described in long QT syndrome type 3, Brugada
syndrome\textsuperscript{51}, familial dilated cardiomyopathy
(DCM).\textsuperscript{52,53} Mutations in \emph{SCN5A} have been
suggested through single gene analyses to be associated with AF
development in both lone AF and AF in the context of structural heart
disease.\textsuperscript{54,55}

Importantly, there is a growing understanding of the overlap between AF
and genetic DCM. The most prominent example is that of
\emph{TTN}cardiomyopathy. \emph{TTN} encodes the largest human protein,
and truncating variants in \emph{TTN} (\emph{TTNtv} ) have previously
been implicated in 25\% of familial cases of DCM\textsuperscript{56} and
linked to increased risk of ventricular
arrhythmias.\textsuperscript{57}Patients with \emph{TTN} DCM are known
to have high rates of AF\textsuperscript{58} and be more likely to
develop persistent AF.\textsuperscript{57} \emph{TTNtv} also appear to
lead to increased risk of AF\textsuperscript{59}, even when controlling
for cardiomyopathy status.\textsuperscript{60} In one population of
familial AF,\emph{TTNtv} were associated with AF onset at median age of
26, and all variants were in the cardiac isoforms of \emph{TTN} . Of
interest, in this analysis, \emph{TTNtv} carriers did not have
echocardiographic evidence of left ventricular (LV) structural
dysfunction and had normal left atrial (LA) and LV dimensions at time of
diagnosis or at follow-up multiple years later.\textsuperscript{61} LOF
variants in \emph{TTN} are more common among patients with early-onset
AF compared to healthy controls\textsuperscript{62}, with a higher
proportion of variants seen in younger patients at time of AF
diagnosis.\textsuperscript{63}Additionally, when compared to all
patients with AF, early-onset AF\emph{TTNtv} carriers are at increased
risk of reduction in left ventricular ejection fraction and left atrial
late gadolinium enhancement on cardiac magnetic resonance imaging, a
marker of atrial fibrosis.\textsuperscript{64}

The success of GWAS at identifying SNPs significantly associated with AF
sparked interest in using polygenic risk scores (PRS) in the clinic. PRS
is calculated by summing over the risk alleles an individual carries,
weighted by the effect size derived from a GWAS, and has been
established for prediction of AF development.\textsuperscript{65} An
analysis of the FinnGenn biobank, which utilizes patients in a large
Finnish database, showed that the top 2.5\% of scorers in an AF PRS
system have a predicted 61\% lifetime risk of
AF.\textsuperscript{66}Another PRS in a largely European, United Kingdom
population demonstrated that a higher PRS modifies a patient's risk of
AF development in addition to the risk that is predicted by traditional
AF risk factors (including hypertension, diabetes, obesity, and
smoking).\textsuperscript{59} This finding was replicated in the
Framingham cohort, where clinical risk factors were shown to further
modify AF risk within individual PRS
subgroups.\textsuperscript{67}Finally, a higher PRS is also associated
with higher risk of AF in\emph{TTN} LOF variant
carriers.\textsuperscript{68} However, there are no current models
combining SNPs and clinical risk factors to predict long-term outcomes
of patients with AF.

\textbf{CLINICAL TESTING CONSIDERATIONS}

Despite the plethora of data supporting genetic risk analysis for the
prediction of AF and increasingly available commercial genetic tests,
contemporary guidelines do not recommend routine genetic testing for
all-comers with AF. The 2014 American Heart Association, American
College of Cardiology, and the Heart Rhythm Society guidelines provide a
class IIb recommendation for consideration of genetic testing in
patients with AF and multigenerational familial
AF.\textsuperscript{19}This is clarified in the Heart Rhythm Society and
the European Heart Rhythm Association consensus statement by citing a
lack of actionable evidence on how genetic analyses, which have largely
focused on AF prediction, will impact clinical AF
outcomes.\textsuperscript{69}

Challenges of Genetic Testing

Genetic testing in all-comers with AF remains challenging for several
reasons, in part due to logistic issues with genetic testing, including
lack of universal access and high financial
cost.\textsuperscript{70}Additionally, there are several AF-specific
factors that limit universal genetic testing among patients with AF, in
addition to lack of clinical outcome data to support its use. Foremost,
widespread genetic testing in AF is limited by an unknown prevalence of
rare, potentially pathogenic variants in all-comers with AF. In patients
with very early-onset lone AF only 15\% may carry a recognized
pathologic mutation in a panel of genetic mutations, including various
ion channel genes, associated with AF development\textsuperscript{30};
this finding has been replicated in broader context of all lone-AF
patients.\textsuperscript{49} These rates are similar in very-early
onset AF patients with regards to \emph{TTN}mutations, with a prevalence
of 16\%.\textsuperscript{71} These estimates are much lower when
considering genes associated with long-QT syndrome\textsuperscript{72}
and laminopathies (which are associated with mutations in Lamin A/C,
nuclear membrane filaments)\textsuperscript{73}, which are associated
with higher rates of AF.\textsuperscript{74,75} Additionally, discovery
of carrier status of these genes in family members does not imply 100\%
penetrance.\textsuperscript{17,76}

Widespread genetic testing in AF has the potential to uncover multiple
variants of uncertain significance (VUS). Yoneda et al. found that in a
cohort of 1,293 early onset AF subjects, 812 (63\%) carried a VUS in an
inherited cardiomyopathy or arrhythmia syndrome
gene.\textsuperscript{49} Universal genetic testing would likely lead to
a high number of VUS detected, and, currently, there is limited data to
adjudicate how these variants affect disease state, which is also a
problem for other inherited cardiomyopathy
syndromes.\textsuperscript{77}Additionally, widespread genetic testing
may be limited by the ability of positive AF family history in
predicting AF occurrence in unaffected family members and in outcomes
for patients with AF. Positive family history of AF confers an
approximate 2-fold relative risk of developing AF in unaffected family
members.\textsuperscript{78} Family history of AF is also more commonly
seen in patients with early-onset lone AF.\textsuperscript{79}
Additionally, a positive family history of AF diagnosed in a
first-degree relative at [?]65 years old is associated with an increased
risk of atrial arrhythmia recurrence in drug-refractory AF
post-ablation.\textsuperscript{80} Similarly, patients with a positive
family history of AF occurring in a first-degree relative [?]65 years old
are more likely to receive a permanent pacemaker or implantable
cardioverter-defibrillator (ICD).\textsuperscript{81} Taken together,
this stresses the importance of gathering a thorough family history in
patients that are newly diagnosed with AF.

Recommendations for Genetic Testing

Genetic testing in AF carries multiple potential benefits, including
early identification of patients who are at high risk for developing an
associated cardiomyopathy and in whom intensified surveillance may be
warranted.\textsuperscript{82} Based on the current available data, we
suggest consideration of genetic testing in selected subsets of the AF
population (Figure 2):

\begin{enumerate}
\tightlist
\item
  Patients with lone AF, defined as \textless{}66 years of age at time
  of AF diagnosis and in the absence of structural heart disease
\item
  Patients without clinical risk factors for AF, such as hypertension,
  chronic kidney disease, or diabetes
\item
  Patients with AF and family history of ICD implantation
\item
  Patients with AF and family history of sudden cardiac death
\item
  Patients with AF and who have multigenerational family history of
  AF\textsuperscript{83}
\end{enumerate}

\textbf{CLINICAL MANAGEMENT CONSIDERATIONS}

Given the growing repository of causative rare genes and linked SNPs
with AF, multiple studies have analyzed the role of specific genetic
variants on outcomes by AF management strategy (rate vs rhythm control;
AAD trial vs ablation). However, outcomes remain variable by variant
analyzed (\textbf{Table 1} ). Additionally, many published studies on
this topic are retrospective, observational studies, and there is a
dearth of prospective, randomized controlled trials to inform the
universal utility of genetic testing and to inform AF care. For example,
there is a paucity of data for surgical treatment in genetically linked
AF. Given lone AF is a well-established clinical phenotype, multiple
studies have analyzed post-operative rhythm-free survival after Cox-Maze
surgery in this population.\textsuperscript{84,85} Among these patients,
Cox-Maze is associated with durable freedom from AF without the use of
AAD.\textsuperscript{86} Although there is a strong genetic association
with lone AF, there have been no direct analyses of genetic variants on
outcomes in surgical AF management.

In contrast, there are some emerging data for the effect of genetic
variation on AF pharmacotherapy response. In acute AF with rapid
ventricular response, it is currently recommended to utilize
atrioventricular nodal blocking agents for symptomatic and heart rate
management.\textsuperscript{86} Only one analysis has evaluated the
response to intravenous diltiazem in rapid ventricular response in
European patients with AF. However, multiple AF susceptibility SNPs
combined into a susceptibility score, including those at 4q25, did not
appear to alter response to acute rate control methods in an emergency
room AF population.\textsuperscript{87} In contrast, the Vanderbilt AF
Registry identified that the wildtype SNP rs10033464 at 4q25 was
associated with a favorable response to anti-arrhythmic drug therapy,
compared to matched controls with a variant allele.\textsuperscript{88}

More supporting evidence has identified that genetic variability
influences outcomes after AF catheter ablation. A variety of SNPs
associated with AF susceptibility have been shown to be associated with
modulation of response to catheter
ablation.\textsuperscript{89-93}Additionally, SNPs associated with
electrical remodeling in lone AF have also been associated with AF
recurrence post ablation,\textsuperscript{94} and there is some emerging
data concerning the effects of atrial cardiomyopathy\textsuperscript{95}
and DCM related variants on post-ablation outcomes.\textsuperscript{96}
By far, SNPs at locus 4q25 have consistently been associated with AF
susceptibility, and there are a number of analyses indicating this
locus' role in response to AF therapy. The SNP rs2200733, which was one
of the first SNPs associated with increased AF susceptibility at 4q25
has been demonstrated to lead to decreased likelihood of arrhythmia-free
survival and increased likelihood of AAD therapy post catheter ablation,
possibly due to altered left atrial conduction
patterns.\textsuperscript{97-99}However, other SNPs, including
rs10033464 (which is associated with increased left atrial
diameter)\textsuperscript{100}, at this locus have not been consistently
associated with AF recurrence post-ablation, including in a
predominantly Turkish-based population\textsuperscript{101} and in
meta-analysis.\textsuperscript{102} There is some conflicting data in
another European population the rs10033464 SNP was associated with AF
recurrence post ablation\textsuperscript{103} and in
meta-analysis.\textsuperscript{100,104} This variability may be
explained in part by variation in increased levels of circulating
biomarkers of myocardial fibrosis in patients with paroxysmal
AF.\textsuperscript{105} Of note, there is emerging evidence that other
SNPs at 4q25 may increase left atrial scar formation and increase
non-pulmonary vein triggers for AF recurrence, which may help inform
future risk stratification when selecting patients for catheter
ablation.\textsuperscript{106} However, prospective analyses of these
and other SNPs are still needed.

While most studies in this space rely on observational data, the
Genotype-Directed Comparative Effectiveness Trial of Bucindolol and
Metoprolol Succinate for Prevention of Symptomatic Atrial
Fibrillation/Atrial Flutter (AFL) in Patients with Heart Failure
(GENETIC-AF) trial was one of the first trials to interrogate the
genotype-outcome relationship. This trial investigated the role of
genotype-guided use of bucindolol versus metoprolol succinate in
reducing the recurrence of symptomatic AF/AFL events and/or mortality in
a population of heart failure with reduced ejection fraction. This trial
was founded on the principle that bucindolol is a non-selective
beta-blocker with particular efficacy in patients with
\emph{ADRB1}Arg389Arg genotype.\textsuperscript{107} Patients managed
with bucindolol had 55\% reduction in AF burden compared to metoprolol
and a 32\% reduction in necessity of rhythm control strategies for those
with recurrent AF/AFL.\textsuperscript{108} This trial represents a
major advance in the use of genotyping to inform therapy selection in
AF/AFL patients and may help inform further trial design surrounding AF
outcomes and other genetic variants.

\textbf{FUTURE DIRECTIONS IN GENETIC AF}

As medical care continues to move towards a personalized,
precision-based approach, genetic testing and recognition of genetically
mediated disease processes will rise to the forefront in medical
diagnosis, treatment, and prognosis. This too includes the recognition
that a sizable proportion of the AF population manifests a genetically
mediated form of AF, and this paradigm is even more true for patients
with early onset or lone AF in the absence of structural heart disease.
While this paradigm shift is in its relative infancy, research is
emerging that will support enhanced recognition and care of these
patients.

At this time, there remains heterogeneity across medical centers as it
relates to which patients are referred for genetic
testing.\textsuperscript{109} The future of this field will rely on the
development of risk stratification models for AF based on genetic
profile, family history, and patient phenotype information; effective
treatment plans based on a patient's genetic profile (including rate
control strategy, medical rhythm control and ablation
therapy)\textsuperscript{110}; and evaluation for long-term progression
of disease based on, likely, a combination of genetic and environmental
factors.\textsuperscript{111} It may bear to reason, as well, that there
are subsets of the AF population that may be at differential risk for
thromboembolic events and stroke when compared to the AF population at
large. While there is emerging data to suggest that AF
PRS\textsuperscript{112, 113} may predict cardioembolic stroke risk,
future prospective studies in this space are needed. Creating a genetic
profile using both common and rare variation is becoming increasingly
affordable with even whole genome sequence data nearly within reach for
many patients. As these costs continue to come down, the medical
community must be prepared to utilize these data. While new research
programs seek to sequence more diverse cohorts, these data are often
completely deidentified with little to no phenotype data. Additional
cohorts with phenotype information are needed to provide fine-tuned
associations across detailed phenotypes. Medical biobanks that
incorporate a subject's complete medical record and genomic profile,
provide a fertile space for medical research and require further
investment.

Among patients with AF as part of a greater cardiomyopathic process,
such as those with \emph{TTN} and Lamin A/C mutations, recognition of an
underlying genetic etiology should heighten awareness and screening for
ventricular tachyarrhythmias and ventricular
dysfunction.\textsuperscript{114} These patients are at increased risk
of not only AF but also non-sustained ventricular tachycardia and
atrioventricular block and would likely benefit from more frequent
arrhythmia monitoring.\textsuperscript{115} If a genetic cardiomyopathy
is suspected, patients should be referred to genetic counseling and, if
appropriate, a cardiologist with experience caring for patients with
genetically mediated cardiomyopathies. Early recognition is important
for future screening in the index patient, as well as for relevant
family screening for arrhythmia and LV dysfunction. The growth of our
understanding of genetic cardiomyopathies and their interaction with AF
presents an exciting new challenge in the care of these patients. As the
field continues to learn more about this subset of patients, we
anticipate the development of diagnostic and therapeutic plans based in
part on a patient's genetic profile.

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\end{enumerate}

\textbf{Table 1: Summary of evidence of influence of genetics on
outcomes in AF catheter ablation}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Citation}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Variant in Gene/Locus}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Study Population}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Outcome Analyzed}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Result}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Wu G, et al.\textsuperscript{89}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\emph{IL6R}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
AAD-refractory AF, Chinese population\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Early (within 1 month) and late (within 1 year) recurrence after
catheter ablation\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Early: OR 1.84 (95\% CI 1.31-2.59, p=4.10x10\textsuperscript{-4}) Late:
OR 1.92 (95\% CI 1.30-2.81, p=0.001)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Cao H, et al.\textsuperscript{90}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{RANKL}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Lone AF, Chinese population\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Recurrence after first-time catheter ablation\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
HR 1.62 (95\% CI 1.37-1.96, p\textless{}0.001) for CG/CC vs GG
genotype\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Wu H, et al.\textsuperscript{93}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{SCN10A}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
AAD-refractory AF, Chinese population\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Recurrence after RFCA\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
OR 0.36 (95\% CI 0.22-0.60, p=7.04x10\textsuperscript{-5}) for
rs6795970; other 14 SNPs not significant\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Choi EK, et al.\textsuperscript{91}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4q25, 16q22, 1q21\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
AF without structural heart disease or prior ablation, Korean
population\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Recurrence after RFCA\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
No significant associations\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Park JK, et al.\textsuperscript{92}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4q25, 16q22, 1q21\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Long-standing persistent AF, Korean population\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Recurrence after RFCA\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
OR 2.70 (95\% CI 1.41-5.14, p=0.003) for rs2106216 of \emph{ZFHX3};
other SNPs not significant\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Wong GR, et al.\textsuperscript{97}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4q25 rs2200733\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
AF without structural heart disease, Predominantly European cohort\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Recurrence after RFCA\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
HR 0.35 (95\% 0.17-0.73, p=0.005) for arrhythmia-free survival in
variant carriers\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Shoemaker MB, et al.\textsuperscript{98}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4q25 rs2200733, rs10033464\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
AF without prior surgical ablation, Vanderbilt AF Registry\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Any atrial arrhythmia after catheter ablation\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Survival time ratio 0.76 (95\% CI 0.60-0.95, p=0.016) for
rs2200733\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Husser D, et al.\textsuperscript{103}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
4q25 rs2200733, rs10033464\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Persistent or AAD-refractory AF, Caucasian population\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Early (within 1 week of ablation) and late AF recurrence (within 6
months) after catheter ablation\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Early OR 2.08 (95\% CI 1.09-3.99, p=0.027) Late OR 2.88 (95\% CI
1.25-6.63, p=0.013) rs2200733 also significant\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Zhao LQ, et al.\textsuperscript{99}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 SNPs in 4q25, 16q22 and NAAP, KCNJ5, and IL6R genes\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Non-lone AF, Chinese population\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Any atrial arrhythmia \textgreater{}3 months after catheter
ablation\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
HR 1.77 (95\% CI 1.06-2.94, p=0.028) for homozygous rs2200733\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Ulus T, et al.\textsuperscript{101}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11 SNPs in \emph{PITX2, ZFHX3, EPHX2, CAV1, TBX5, TGF-1, and
SCN10A}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
AF without severe structural heart disease, Turkish population\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Any atrial arrhythmia after cryoballoon ablation\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
OR 4.50 (95\% CI 1.04-19.31, p=0.043) for rs3807989\_G in
\emph{CAV1}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{*Abbreviations:} AF, atrial fibrillation; AAD, antiarrhythmic
drug; OR, odds ratio; CI, confidence interval; RFCA, radiofrequency
catheter ablation; SNP, single nucleotide polymorphism

\textbf{Figure 1: Summary list of select single genes and SNPs
implicated in genetic AF}

\textbf{Legend:} Orange: select single genes (including ion channel
genes) associated with AF in familial and single gene analyses; Green:
select loci associated with AF in GWAS; Blue: cardiomyopathy genes
associated with AF risk in multiple study designs. Of note, each gene
may be identified by multiple different genetic analysis types.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 2: Suggested algorithm for genetic testing in AF}

\textbf{Legend:} Stepwise approach to diagnosis and management of
genetic AF. In addition to traditional one-time or ambulatory
electrocardiogram and transthoracic echocardiogram, patients with newly
diagnosed AF should have a detailed family history of AF (including time
of onset), sudden cardiac death, and ICD taken. Patients with
significant personal or family history should undergo genetic testing,
and, if positive, be referred for further counseling by a cardiologist
specializing in genetics.

\selectlanguage{english}
\FloatBarrier
\end{document}

