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European Journal of Human Genetics logoLink to European Journal of Human Genetics
. 2013 Jul 10;22(3):297–306. doi: 10.1038/ejhg.2013.139

Atrial fibrillation: the role of common and rare genetic variants

Morten S Olesen 1,2,4,*, Morten W Nielsen 1,2,4, Stig Haunsø 1,2,3, Jesper H Svendsen 1,2,3
PMCID: PMC3925267  PMID: 23838598

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting 1–2% of the general population. A number of studies have demonstrated that AF, and in particular lone AF, has a substantial genetic component. Monogenic mutations in lone and familial AF, although rare, have been recognized for many years. Presently, mutations in 25 genes have been associated with AF. However, the complexity of monogenic AF is illustrated by the recent finding that both gain- and loss-of-function mutations in the same gene can cause AF. Genome-wide association studies (GWAS) have indicated that common single-nucleotide polymorphisms (SNPs) have a role in the development of AF. Following the first GWAS discovering the association between PITX2 and AF, several new GWAS reports have identified SNPs associated with susceptibility of AF. To date, nine SNPs have been associated with AF. The exact biological pathways involving these SNPs and the development of AF are now starting to be elucidated. Since the first GWAS, the number of papers concerning the genetic basis of AF has increased drastically and the majority of these papers are for the first time included in a review. In this review, we discuss the genetic basis of AF and the role of both common and rare genetic variants in the susceptibility of developing AF. Furthermore, all rare variants reported to be associated with AF were systematically searched for in the Exome Sequencing Project Exome Variant Server.

Keywords: lone AF, GWAS, PITX2

Introduction

Atrial fibrillation (AF) is a common supraventricular arrhythmia affecting 1–2% of the general population. The prevalence is increasing and is estimated to be doubled by 2040.1, 2 In most cases, AF is associated with cardiac risk factors such as hypertensive, ischemic and/or structural heart disease.3, 4 However, a subgroup of patients presents with AF in the absence of predisposing factors, a condition called ‘lone AF', accounting for 10–20% of the total number of patients with AF.5

The mechanisms underlying AF are not fully understood but a heterogeneous model, based on the interaction of multiple substrates and triggers, is thought to underlie the pathophysiology of the disease. Lone AF has been suggested to be a primary electrical disease caused by disturbances in ionic currents and a genetic cause of these types of electrical disturbances is becoming increasingly recognized.6

A number of studies have demonstrated that AF and in particular lone AF have a substantial genetic component.7, 8, 9, 10, 11, 12, 13 Oyen et al14 have recently shown that an individual's risk of developing lone AF at a young age, increases drastically with both increasing number of relatives with lone AF and decreasing age at onset of the disease in these relatives, indicating an underlying genetic component in early onset lone AF.

Evidence for a heritable component of more common forms of AF has only recently been recognized. Fox et al11 studied the inherited predisposition for AF in >5000 individuals and showed that, the development of AF in the offspring was independently associated with parental AF. Offspring of parents with AF had approximately a doubled 4-year risk of developing AF, even after adjusting for known risk factors such as hypertension, diabetes and myocardial infarction.

In this review, we discuss the genetic basis of AF and the role of both common and rare genetic variants in the susceptibility of developing AF.

Materials and methods

The review is based on an information retrieval carried out in Pubmed using the MeSH database and Google Scholar. A systematic literature search was performed to identify all studies published before April 2013, which investigated the genetic basis of AF. Searching with the query ((‘Atrial fibrillation' (MeSH)) OR (atrial fibrillation)) AND ((‘Genetics' (MeSH)) OR (genetic*)) AND ((‘Mutation' (MeSH)) OR (mutation*) OR (‘Polymorphism, single nucleotide' (MeSH)) OR (polymorphism, single nucleotide) OR (monogenic*) OR (GWAS)) yielded 527 articles. Only articles concerning the genetic basis of AF were included in this review. Small studies concerning common variants in genes not associated with AF were excluded, unless these studies have been replicated in other independent populations or convincing electrophysiology was presented, because of a high risk of false-positive associations. The reference list and related articles of each relevant publication were also examined to identify additional studies appropriate for inclusion in this literature study. Furthermore, rare variants associated with AF were systematically search for existence in NHLBI GO Exome Sequencing Project (ESP). The reference sequences used are: NM_000218 (KCNQ1), NM_000219 (KCNE1), NM_172201 (KCNE2), NM_005472 (KCNE3), NM_080671 (KCNE4), NM_012282 (KCNE5), NM_004980 (KCND3), NM_000238 (KCNH2), NM_000891 (KCNJ2), NM_004982 (KCNJ8), NM_002234 (KCNA5), NM_005691 (ABCC9), NM_198056 (SCN5A), NM_001037 (SCN1B), NM_199037 (SCN1Bb), NM_004588 (SCN2B), NM_018400 (SCN3B), NM_153485 (NUP155), NM_000165 (GJA1), NM_005266 (GJA5), NM_006172 (NPPA), NM_002052 (GATA4), NM_005257 (GATA6), NM_005572 (LMNA), NM_004387 (NKX2-5) and NM_022469 (GREM2).

Results

The role of common genetic variants

In recent years, genome-wide association studies (GWAS) have indicated that common single-nucleotide polymorphisms (SNPs) have a role in the development of AF. The first GWAS on AF showed that a SNP (rs2200733) located in proximity of the gene PITX2 on chromosome 4q25 was highly associated with AF.15 Since then, a number of GWAS have identified new SNPs associated with AF.16, 17, 18 The GWAS linking these SNPs to AF were all performed in general AF populations and the biological pathway between the SNPs and the emergence of AF still remains to be solved.

In the following, current knowledge about the individual SNPs and their possible involvement in the pathogenesis of AF will shortly be presented (see Table 1).

Table 1. Summary of SNPs associated with AF.

SNP Chromosome locus Hg location Closest gene Location of SNP Reference
rs2200733 4q25 4:111 710 169 PITX2 150-kb upstream 15
rs2106261 16q22 16:73 051 620 ZFHX3 Intronic 16
rs13376333 1q21 1:154 814 353 KCNN3 Intronic 17
rs3807989 7q31 7:116 186 241 CAV1/CAV2 Intronic 18
rs3903239 1q24 1:170 569 317 PRRX1 46-kb upstream 18
rs1152591 14q23 14:64 680 848 SYNE2 Intronic 18
rs10821415 9q22 9:97 713 459 C9orf3 Intronic 18
rs7164883 15q24 15:73 652 174 HCN4 Intronic 18
rs10824026 10q22 10:75 421 208 SYNPO2L 5-kb upstream 18
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All from GWAS.

The 4q25 locus

The SNP rs2200733 resides closest to the gene PITX2 encoding the paired-like transcription factor PITX2. It was the first SNP to be identified and has been the top hit in all GWAS. Substantial research has therefore been focusing on this gene. In the human heart, PITX2c is the major isoform expressed19 and is involved in the control of asymmetric cardiac morphogenesis.15, 20 Chung et al21 have shown the association of a genetic variant on chromosome 4q25 with levels of PITX2c transcripts in left atrial tissue samples and knockout mouse models have indicated a critical role of the PITX2c in the development of the left atrium.22 Of note, PITX2c was in a recent study demonstrated to be a requisite for the development of a sleeve of cardiomyocytes extending from the left atrium to the initial portion of the pulmonary veins, which is believed to be the anatomical substrate for AF and the fundament for pulmonary vein isolation when an ablation strategy is chosen in an AF patient.23 In line with this, clinical and animal studies have demonstrated that ectopic foci of electrical activity arising from within the pulmonary veins and posterior left atrium have a substantial role in initiating and maintaining fibrillatory activity.24, 25 In contrast to studies indicating a structural role of PITX2c, a recently published study of heterozygous knockout (PITX2c+/−) mice showed that these mice have a normal cardiac morphology and function, whereas expression of calcium ion binding proteins, gap- and tight junctions and ion channels was changed. They furthermore showed that isolated PITX2c+/− mice hearts were susceptible to AF during programmed pacing, because of shortening of atrial action potential durations (APDs) and the effective refractory period (ERP).26 In line with these results, human studies have recently revealed that PITX2c expression is significantly decreased in patients with sustained AF, thus providing a molecular link between PITX2 loss-of-function and AF.27 Although a lot of studies indicate PITX2 as having a role in AF, evidence regarding the expression of PITX2 and its target genes in patients with AF is still missing. For instance, no studies regarding mRNA levels in atrial tissue of PITX2 and target proteins measured by qPCR are available. For further insight and overview figures for the role of PITX2 in AF pathogenesis, please see Liu et al28 and Xiao et al.29

Other GWAS loci

The SNP rs2106261 is located on chromosome 16q22 in an intronic region of transcription factor ZFHX3. The function of ZFHX3 in cardiac tissue is unknown but it is expressed in mouse hearts.30 The SNP rs13376333 is located on chromosome 1q21 in KCNN3, which encodes a calcium-activated potassium channel involved in atrial repolarization. In a rabbit burst-pacing model mimicking ectopic pulmonary vein foci, the pulmonary vein and atrial APD was shortened. This APD shortening was inhibited by apamin, a blocker of the calcium-activated potassium channels.31 This provides a possible basis of KCNN3 having a role in AF. The SNP rs3807989 is located close to the gene CAV1-encoding caveolin. CAV1 is expressed in atrial myocytes and is necessary for the development of caveolae involved in electric signal transduction.32 CAV1 knockout mice develop dilated cardiomyopathy and pulmonary hypertension.33 The SNP rs3903239 is located on chromosome 1q24, 46-kb upstream from the closest gene PRRX1 encoding a homeodomain transcription factor highly expressed in the developing heart.18 Knock-out mouse models have revealed that PRRX1 is necessary for the normal development of great vessels and lung vascularization.34, 35 The SNP rs1152591 is located on chromosome 14q23, in an intron of the gene SYNE2encoding nesprin 2, which is a linker of nucleoskeleton and cytoskeleton (LINC) protein involved in maintaining cellular architecture and nuclear integrity.36 It is highly expressed in heart and skeletal muscle, and mutations in SYNE2 have been identified in families with Emery–Dreifuss muscular dystrophy. A disease that also displays cardiac manifestations characterized by cardiomyopathy and cardiac conduction defects.18, 37 The SNP rs10821415 is located in an open reading frame on chromosome 9. Genes near this locus is FBP1 and FBP2, which is involved in gluconeogenesis.18 How this SNP could be involved in developing AF remains unknown. The SNP rs7164883 is located on chromosome 15q24 in an intron of the gene HCN4, which encodes the cardiac pacemaker channel responsible for the funny current (If). The HCN4 channel is expressed in most of the conduction system and is the predominant isoform of the primary pacemaker in mouse hearts.38 Mutations in HCN4 have been associated with sinus node dysfunction.39, 40 The SNP rs10824026 is located on chromosome 10q22, 5-kb upstream of SYNPO2L.18 Beqqali et al41 identified the gene as encoding a cytoskeletal protein, which is highly expressed in the Z-disc of cardiac and skeletal muscle. They renamed it CHAP, cytoskeletal heart-enriched actin-associated protein. CHAP was found to have an important role in skeletal and cardiac muscle development. Of note, Brugada et al42 identified the SYNPO2L locus as a susceptibility locus for AF in a family with autosomal dominant AF.

None of the GWAS hits are found in amino-acid-coding regions of the genes. One possible explanation for the association with AF is that these variants may function as regulators of an adjacent gene, perhaps by altering the function of a promoter or enhancer and thereby causing an up or downregulation of genes nearby. Intense research is ongoing in order to correlate the GWAS hits with mRNA expression of genes located in proximity of the regions where the SNPs resides. These research projects are complicated by the fact that the top hits from GWAS are not necessarily the disease causative variants and other variants in high linkage must also be taken into account. Furthermore, it is possible that a GWAS hit is in high linkage disequilibrium (LD) with a low frequent variant, as was shown to be the case for a variant associated with sick sinus syndrome.43 Thus, so far the mechanisms behind the association of the GWAS hits and AF still remain unresolved.

The role of rare genetic variants

Several genetic reports have revealed rare variants associated with AF in genes encoding cardiac gap junctions, signaling molecules, ion channels and accessory subunits.6 Most of these studies show either gain- or loss-of-function mutations in the genes encoding proteins contributing to cardiac depolarization or repolarization leading to increased susceptibility of AF.

These results support the two current conceptual models for AF. The first one being that cardiac action potential (cAP) shortening functions as a substrate for re-entry wavelets in the atria.44, 45 The second one being that a prolonged ERP enhances the propensity for early afterdepolarization (EAD) and thereby, increasing the susceptibility to AF.46 For a general introduction to cAP and involved ion channels, please see Nattel44 and/or Shiroshita-Takeshita et al.47

In the following, current knowledge about rare variants in the individual genes and their possible involvement in the pathogenesis of AF will be presented.

Potassium channel mutations

Chen et al48 revealed the first association between mutations in KCNQ1 and familial AF (see Table 2). The KCNQ1 gene encodes the pore-forming α-subunit of the cardiac potassium channel IKs involved in cardiac repolarization. They studied a four-generation Chinese family with AF and indentified a mutation in all of the affected family members. Functional studies showed an increase in current density and altered gating and kinetic properties. This suggests a gain-of-function effect resulting in shortening of APD and reduction of the ERP.6 A number of gain-of-function mutations in KCNQ1 have been identified since (see Table 2).49, 50, 51, 52, 53 Just recently, Bartos et al54 identified a gain-of-function mutation in KCNQ1 with high penetrance in five different families with early-onset AF. In addition to AF, several of the family members had abnormal QTc intervals, syncope or experienced sudden cardiac arrest or death.

Table 2. Summary of potassium channel rare variants associated with AF.

Gene Gene product Nucleotide substitution Amino-acid substitution Documented family co-segregation Electrophysiological consequence Reference Found in ESP EA minor/minor/ minor/major Found in ESP AA minor/minor/ minor/major Found in ESP all minor/minor/ minor/major
KCNQ1 α-Subunit of IKs c.40C>T p.(Arg14Cys) Yes Gain-of-function 53 0/0 0/0 0/0
    c.160_168insATCGCGCCC p.(54_56insIleAlaPro) Yes Gain-of-function 52 0/0 0/0 0/0
    c.418A>G p.(Ser140 Gly) Yes Gain-of-function 48 0/0 0/0 0/0
    c.421G>A p.(Val141Met) No Gain-of-function 49 0/0 0/0 0/0
    c.625C>T p.(Ser209Pro) Yes Gain-of-function 50 0/0 0/0 0/0
    c.692G>A p.(Arg231His) Yes Gain-of-function 54 0/0 0/0 0/0
    c.693C>T p.(Arg231Cys) Yes Gain-of-function 51 0/0 0/0 0/0
KCNE1 β-Subunit of IKs c.74C>T p.(Gly25Val) No Gain-of-function 55 0/0 0/0 0/0
    c.179G>A p.(Gly60Asp) Yes Gain-of-function 55 0/0 0/0 0/0
KCNE2 β-Subunit of IKs c.79C>T p.(Arg27Cys) Yes Gain-of-function 56 0/0 0/0 0/0
KCNE3 β-Subunit of IKs c.49G>A p.(Val17Met) No Gain-of-function 12 0/0 0/0 0/0
KCNE4 β-Subunit of IKs c.422A>C p.(Glu141Ala) ? Possible change 57 0/5 0/0 0/5
KCNE5 β-Subunit of IKs c.193C>T p.(Leu65Phe) No Gain-of-function 13 0/0 0/0 0/0
KCND3 Kv4.3 c.5C>A p.(Ala2Glu) ? No change 57 0/0 0/0 0/0
    c.641A>G p.(Lys214Arg) ? No change 57 0/4 0/0 0/4
    c.1633G>C p.(Ala545Pro) ? Gain-of-function 118 0/0 0/0 0/0
KCNH2 α-Subunit of IKr c.526C>T p.(Arg176Trp) No Loss-of-function 57, 121 0/0 0/0 0/0
    c.1330G>A p.(Glu444Lys) Yes Loss-of-function 57 0/0 0/0 0/0
    c.1764C>G p.(Asn588Lys) Yes Gain-of-function 58, 59 0/0 0/0 0/0
KCNJ2 Kir2.1 c.277G>A p.(Val93Ile) Yes Gain-of-function 60 0/2 0/1 0/3
KCNJ8 Kir6.1 c.1265C>T p.(Ser422Leu) ? Gain-of-function 61, 62 0/19 0/1 0/20
KCNA5 Kv1.5 c.143A>G p.(Glu48Gly) No Gain-of-function 66 0/0 0/0 0/0
    c.211_243 p.(71_81del) Yes Loss-of-function 65 NA NA NA
    c.464A>G p.(Tyr155Cys) No Loss-of-function 66 0/0 0/0 0/0
    c.913G>A p.(Ala305Thr) Yes Gain-of-function 66 0/0 0/0 0/0
    c.964G>C p.(Asp322His) No Gain-of-function 66 0/0 0/0 0/0
    c.1123G>T p.(Glu375Ter) Yes Loss-of-function 63 0/0 0/0 0/0
    c.1407C>A p.(Asp469Glu) No Loss-of-function 66 0/0 0/0 0/0
    c.1462C>T p.(Pro488Ser) No Loss-of-function 66 0/0 0/0 0/0
    c.1580C>T p.(Thr527Met) Yes Loss-of-function 46, 64 0/0 0/0 0/0
    c.1703G>T p.(Gly568Val) Yes Gain-of-function 57 0/3 0/0 0/3
    c.1727C>T p.(Ala576Val) Yes Loss-of-function 46 0/0 0/0 0/0
    c.1828G>A p.(Glu610Lys) Yes Loss-of-function 46 0/0 0/0 0/0
ABCC9 KATP channel c.4640C>T p.(Thr1547Ile) ? Loss-of-function 67 0/0 0/0 0/0
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Abbreviations: AA, African American; EA, European American; ESP, NHLBI GO Exome Sequencing Project; NA, data regarding major InDel is not available in EVS.

The regulatory β-subunits of the IKs channel are encoded by five genes, KCNE1–5. In a recent study by Olesen et al55 two non-synonymous mutations in KCNE1 was associated with AF. In heterologous expression systems, both mutations showed significant gain-of-function for IKs. Yang et al56 evaluated 28 unrelated Chinese kindred's with AF and identified a mutation in two probands in the KCNE2 gene. The mutation showed a gain-of-function effect on IKs. Lundby et al12 identified a mutation in KCNE3 in a patient with lone AF and electrophysiological recordings displayed a gain-of-function effect on IKs. Recently, a mutation in KCNE4 was identified by Mann et al57 in a patient with AF. The functional consequence of this mutation is uncertain but the authors describe a possible change in IKs, IKr and Ito. Finally, Ravn et al.13 found a missense mutation in KCNE5 in 1 of 158 AF patients resulting in a gain-of-function effect on IKs.

The KCNH2 gene encodes the α-subunit of IKr. A mutation in this gene was identified by Hong et al58 in a family with both short QT and AF, which suggest an overlap in phenotypes. Previously, the mutation has been shown to drastically increase IKr and thus displaying gain-of-function.59 Mann et al57 have revealed additional mutations in KCNH2 in AF patients (see Table 2).

The KCNJ2 gene encodes the inward rectifier channel Kir2.1 that mediates the current IK1 involved in both the late phase of repolarization (phase 3) and the phase of maintaining resting membrane potential (phase 4). Xia et al60 identified a missense mutation in KCNJ2 in a Chinese kindred. Functional analysis of the mutant demonstrated a gain-of-function consequence on the Kir2.1 current.

Recently, Delaney et al61 found a missense mutation in KCNJ8 in a cohort of lone AF patients. The KCNJ8 gene encodes the cardiac KATP channel Kir6.1. The Kir6.1 channel facilitates a non-voltage-gated inwardly rectifying potassium current, leading to a shortening of the APD under conditions of metabolic stress.61 In a previous study, the mutation was shown to display a gain-of-function effect.62

The KCNA5 gene encodes the atria-specific Kv1.5 channel responsible for the ultra-rapid delayed rectifier potassium current, IKur, involved in cardiac repolarization. Olson et al63 identified a nonsense mutation in a familial case of AF. The mutation displayed a loss-of-function effect resulting in action potential prolongation and EAD. A number of mutations have since then been identified (see Table 2).46, 64, 65, 66

The ABCC9 gene encodes the SUR2A KATP channel subunit involved in maintaining electrical stability under stress, including adrenergic challenge. Olson et al67 identified a missense mutation in the ABCC9 gene in a female case with early-onset AF originating from the vein of Marshall. The mutation displayed loss-of-function.

Sodium channel mutations

The SCNA5 gene encodes the α-subunit of the cardiac sodium channel responsible for the INa current involved in cardiac depolarization (see Table 3). Darbar et al68 identified rare variants in SCN5A in familial form of AF. Interestingly, several of the variants caused overlapping phenotypes with cardiomyopathy. Recently, Olesen et al69 identified eight mutations in SCN5A in a cohort of lone AF patients. Functional investigations of the mutations revealed both compromised transient peak current and increased sustained current. These results indicate that both gain- or loss-of-function alterations in cardiac sodium current are involved in early-onset AF.

Table 3. Summary of sodium channel rare variants associated with AF.

Gene Gene product Nucleotide substitution Amino-acid substitution Documented family co-segregation Electrophysiological consequence Reference Found in ESP EA minor/minor/minor/major Found in ESP AA minor/minor/minor/major Found in ESP all minor/minor/minor/major
SCN5A α-Subunit of INa c.414G>A p.(Met138Ile) Yes Not investigated 68 0/0 0/1 0/1
    c.647C>T p.(Ser216Leu) ? Gain-of-function 68, 122 0/11 0/1 0/12
    c.659C>T p.(Thr220Ile) No Loss-of-function 69, 122 0/4 0/0 0/4
\   c.1018C>G p.(Arg340Gln) No Loss-of-function 69 0/0 0/0 0/0
    c.1127G>A p.(Arg376His) ? Not investigated 68 0/1 0/0 0/1
    c.1282G>A p.(Glu428Lys) Yes Not investigated 68 0/2 0/0 0/2
    c.1333C>G p.(His445Asp) Yes Not investigated 68 0/0 0/0 0/0
    c.1381T>G p.(Leu461Val) Yes Not investigated 68 0/2 0/34 0/36
    c.1410C>G p.(Asn470Lys) Yes Not investigated 68 0/0 0/0 0/0
    c.1441C>T p.(Arg481Trp) ? Not investigated 68 0/0 0/39 0/39
    c.1571C>A p.(Ser524Tyr) ? Not investigated 68 0/7 5/125 5/132
    c.1715C>A p.(Ala572Asp) Yes Not investigated 68 0/20 0/1 0/21
    c.1852C>T p.(Leu618Phe) ? Not investigated 68 0/0 0/27 0/27
    c.1963G>A p.(Glu655Lys) Yes Not investigated 68 0/0 0/0 0/0
    c.2989G>T p.(Ala997Ser) ? Gain-of-function 68, 123 0/0 0/0 0/0
    c.3157G>A p.(Glu1053Lys) ? Not investigated 68 0/0 0/0 0/0
    c.3392C>T p.(Thr1131Ile) No Not investigated 68 0/0 0/1 0/1
    c.3578G>A p.(Arg1193Gln) ? Gain-of-function 68, 122 0/11 0/0 0/11
    c.3823G>A p.(Asp1275Asn) Yes Loss-of-function 124 0/0 0/0 0/0
    c.3911C>T p.(Thr1304Met) No Gain-of-function 69 0/4 0/1 0/5
    c.4478A>G p.(Lys1493Arg) Yes Gain-of-function 125 0/0 0/0 0/0
    c.4786T>A p.(Phe1596Ile) ? No change 69 0/0 0/0 0/0
    c.4877G>A p.(Arg1626His) No Combined 69 0/0 0/0 0/0
    c.5455G>A p.(Asp1819Asn) No Combined 69 0/0 0/0 0/0
    c.5476C>T p.(Arg1826Cys) No Not investigated 68 0/1 0/0 0/0
    c.5624T>C p.(Met1875Thr) Yes Gain-of-function 126 0/0 0/0 0/0
    c.5689C>T p.(Arg1897Trp) No Loss-of-function 69 0/3 0/0 0/3
    c.5851G>A p.(Val1951Met) Yes Gain-of-function 68, 69 0/0 0/0 0/0
    c.5958C>A p.(Asn1986Lys) Yes Loss-of-function 127 0/0 0/0 0/0
    c.6010T>C p.(Phe2004Leu) ? Gain-of-function 68, 122 1/24 0/2 1/26
SCN1B β-Subunit of INa c.254G>A p.(Arg85His) No Loss-of-function 70 0/0 0/0 0/0
    c.457G>A p.(Asp153Asn) No Loss-of-function 70 0/0 0/0 0/0
SCN1Bb β-Subunit of INa c.641G>A p.(Arg214Gln) No Loss-of-function 74, 75 0/21 0/2 0/23
SCN2B β-Subunit of INa c.82C>T p.(Arg28Trp) No Loss-of-function 70 0/1 0/0 0/1
    c.83G>A p.(Arg28Gln) Yes Loss-of-function 70 0/0 0/0 0/0
SCN3B β-Subunit of INa c.17G>A p.(Arg6Lys) No Loss-of-function 72 0/0 0/0 0/0
    c.29T>C p.(Leu10Pro) No Loss-of-function 72 0/0 0/1 0/1
    c.389C>T p.(Ala130Val) ? Loss-of-function 71 0/0 0/0 0/0
    c.482T>C p.(Met161Thr) No Loss-of-function 72 0/0 0/0 0/0
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Abbreviations: AA, African American; EA, European American; ESP, NHLBI GO Exome Sequencing Project.

SCN1B-4B encodes the modifying β-subunits (Navβ1–β4) of the cardiac sodium channel. Watanabe et al70 found two non-synonymous loss-of-function mutations in SCN1B and two in SCN2B in a cohort of 480 AF patients. Wang et al71 found a loss-of-function mutation in SCN3B in another lone AF cohort. Moreover, Olesen et al72 identified three non-synonymous mutations in SCN3B, which displayed a loss-of-function effect in the sodium current. One of the variants p.(Leu10Pro) has also been identified in a patient with Brugada syndrome (BrS).73

SCN1Bb encodes a second β1 transcript, named Navβ1B. Olesen et al74 identified a missense mutation in SCN1Bb in two patients with lone AF as well as one patient with BrS. The same mutation was identified by Hu et al75 in another BrS patient and functional data revealed that the mutation resulted in a 57% decrease in the peak sodium current while the Kv4.3 current was increased by 71% suggesting a combined effect with loss-of-function of the sodium channel current and a gain-of-function of the transient outward potassium current. On this basis, mutations in SCN1Bb could be susceptible variants for both AF and/or BrS.

Non-ion channel mutations

The NUP155 gene encodes a nucleoporin, an essential component of the nuclear pore complex, a complex involved in nucleo-cytoplasmic transport (see Table 4). The gene is located on chromosome 5q13.76 Oberti et al77 mapped an AF locus to chromosome 5q13 in a large AF family with an autosomal recessive inheritance pattern. Subsequently, Zhang et al78 revealed that the above mentioned locus was NUP155 and identified a homozygous mutation in NUP155 in all the affected family members. Heterozygous (NUP155+/−) knockout mice showed AF phenotype.

Table 4. Summary of non-ion channel rare variants associated with AF.

Gene Gene product Nucleotide substitution Amino-acid substitution Documented family co-segregation Electrophysiological consequence Reference Found in ESP EA minor/minor/ minor/major Found in ESP AA minor/minor/ minor/major Found in ESP all minor/minor/ minor/major
NUP155 Nucleoporin c.1172G>A p.(Arg391His) Yes Loss-of-function 77, 78 0/0 0/0 0/0
GJA1 Connexin43 c.932delC Frameshifta No Loss-of-function 93 0/0 0/0 0/0
GJA5 Connexin40 c.113G>A p.(Gly38Asp)a No Loss-of-function 94 0/0 0/0 0/0
    c.145C>T p.(Gln49Ter) Yes Loss-of-function 97 0/0 0/0 0/0
    c.223A>T p.(Ile75Phe) Yes Loss-of-function 98 0/0 0/0 0/0
    c.253G>A p.(Val85Ile) Yes Not investigated 96 0/0 0/0 0/0
    c.262C>T p.(Pro88Ser)a No Loss-of-function 94 0/0 0/0 0/0
    c.286G>T p.(Ala96Ser) No Loss-of-function 94 0/0 0/0 0/0
    c.487A>G p.(Met163Val)a No Loss-of-function 94 0/0 0/0 0/0
    c.661C>A p.(Leu221Ile) Yes Not investigated 96 0/0 0/0 0/0
    c.685C>A p.(Leu229Met) Yes Not investigated 96 0/0 0/0 0/0
NPPA ANP c.190A>C p.(Ser64Arg) Yes Gain-of-function 52 0/24 0/2 0/26
    c.350C>T p.(Ala117Val) Yes Not investigated 117 0/0 0/0 0/0
    c.456_457delAA Frameshift Yes Gain-of-function 80 0/0 0/0 0/0
GATA4 Transcription factor c.46G>T p.(Gly16Cys) Yes Loss-of-function 84 0/0 0/0 0/0
    c.82C>G p.(His28Asp) Yes Loss-of-function 84 0/0 0/0 0/0
    c.112T>G p.(Tyr38Asp) Yes Loss-of-function 85 0/0 0/0 0/0
    c.209G>C p.(Ser70Thr) Yes Loss-of-function 83 0/0 0/0 0/0
    c.307C>G p.(Pro103Ala) Yes Loss-of-function 85 0/0 0/0 0/0
    c.479G>C p.(Ser160Thr) Yes Loss-of-function 83 0/0 0/0 0/0
    c.1294C>T p.(Met247Thr) Yes Not investigated 82 0/0 0/0 0/0
    c.1786C>T p.(Ala411Val) No Not investigated 82 0/12 0/10 0/22
GATA6 Transcription factor c.617A>C p.(Gln206Pro) Yes Not investigated 86 0/0 0/0 0/0
    c.704A>C p.(Tyr235Ser) Yes Loss-of-function 87 0/0 0/0 0/0
    c.795C>G p.(Tyr265Ter) Yes Not investigated 86 0/0 0/0 0/0
    c.1406G>T p.(Gly469Val) Yes Loss-of-function 88 0/0 0/0 0/0
LMNA Lamin A/C c.78C>T p.(Ile26Ile) ? ? 91 0/2 0/0 0/2
    c.832G>A p.(Ala278Thr) Yes Not investigated 90 0/0 0/0 0/0
    c.1462A>C p.(Thr488Pro) No Not investigated 128 0/0 0/0 0/0
    c.1583C>T p.(Thr528Met) Yes Not investigated 91 0/0 0/0 0/0
NKX2-5 Transcription factor c.434T>C p.(Phe145Ser) Yes Not investigated 117 0/0 0/0 0/0
GREM2 BMP antagonist c.226C>G p.(Gln76Glu) No Increase in inhibitory effect 92 0/27 0/4 0/31
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Abbreviations: AA, African American; EA, European American; ESP, NHLBI GO Exome Sequencing Project.

a

Somatic mutations.

NPPA encodes atrial natriuretic peptide, a circulating hormone produced in cardiac atria involved in the regulation of blood pressure through natriuresis, diuresis and vasodilatation.79 Hodgson-Zingman et al80 described a family with AF and an autosomal dominant pattern of inheritance. In this family, a heterozygous frameshift mutation in NPPA was detected and the mutation co-segregated with AF. The mutant peptide was shown to shorten atrial APD and the ERP in a rat heart model. Recently, Abraham et al52 found a novel missense mutation in NPPA that was shown to co-segregate with early-onset AF. In the same cohort, the investigators found a KCNQ1 mutation and functional analysis of the two mutations yielded strikingly similar IKs gain-of-function effects.

The GATA4 and GATA6 genes encode cardiac transcription factors. They work synergistically with NKX2-5 in regulation of target gene expression, especially those involved in cardiogenesis.81 Posch et al82 found a GATA4 mutation in one patient with familial lone AF in a lone AF cohort. A second mutation was found in a patient with sporadic lone AF. Additional studies have identified mutations in GATA4 in different families, which co-segregated with AF and displayed decreased transcriptional effect.83, 84, 85 Yang et al86 reported two heterozygous GATA6 mutations in two of 110 probands with familial AF. Each mutation co-segregated with AF transmitted as an autosomal dominant trait. The mutation was also associated with congenital cardiac defects in three AF patients in the families of the two probands. Additional studies have identified novel mutations in GATA6 that co-segregated with AF and resulted in decreased transcriptional activity.87, 88

The LMNA gene encodes lamin A/C, an intermediate filament protein associated with the inner nuclear membrane. Mutations in this gene have been associated with many diseases such as dilated cardiomyopathy and muscular dystrophy.89 Beckmann et al90 identified a heterozygous missense mutation in LMNA in a family with AF as well as SVT, VF, muscle weakness and sudden cardiac death. Just recently, Saj et al91 found two variants in two unrelated probands with AF, one of them with episodes of AV-block, the other with reduced left ventricular contractile function (ejection fraction of 30%), left bundle branch block and family history of heart disease.

The GREM2 gene encodes the bone morphogenetic protein (BMP) antagonist gremlin-2. Just recently, Müller et al92 identified a variant in GREM2 in two probands of a lone AF cohort. The variant was twofold more potent in antagonizing BMP than wild type. In a zebra fish model GREM2 was shown to be required for cardiac laterality and atrial differentiation. GREM2 over activity resulted in slower cardiac contraction rates and slower contraction velocity. Interestingly, PITX2 (the top hit in GWAS) is regulated by BMP, suggesting that GREM2 is acting upstream PITX2.

Somatic mutations

The GJA1 and GJA5 genes encode connexin43 and connexin40, respectively, which are gap-junction proteins in the atrial myocardium responsible for cell-to-cell conduction of the action potential (see Table 4). Thibodeau et al93 identified a frameshift mutation, caused by a single-nucleotide deletion in GJA1, in atrial tissue in 1 of 10 unrelated lone AF patients. The mutation was absent from lymphocyte DNA of the patient indicating genetic mosaicism. The mutant protein demonstrated a trafficking defect leading to an intracellular retention of the protein and a failure of electric coupling between cells. Gollob et al94 identified four heterozygous missense mutations in GJA5 in 4 of 15 idiopathic AF patients. Of note, in three of the patients the mutations were found to be somatic, suggesting that such mutations also could be involved in AF susceptibility. The mutant proteins revealed impaired intracellular transport or reduced intercellular electrical coupling. This may lead to conduction heterogeneity and re-entrant circuits. Recently, Christophersen et al95 replicated the germline mutation in GJA5 (p.(Ala96Ser)), first detected by Gollob et al94. Yang et al96, 97 and Sun et al98 have identified additional germline mutations in GJA5 (see Table 4).

Bioinformatics

With the recently published exome data from the NHLBI GO ESP, knowledge regarding genetic variation in the general population has become available. ESP currently holds genetic information on approximately 6500 (2200 African Americans and 4300 European Americans) unrelated individuals obtained by next-generation sequencing (NGS) of DNA from individuals recruited from different population studies.99 No clinical data except from ethnicity were available in the ESP population, nor on request. Refsgaard et al100, 101, 102, 103 have recently conducted a number of studies that indicate that the exome database is representative for genetic variation in healthy subjects. All rare variants so far associated with AF (see Tables 2, 3, 4) and hypothesized to be important susceptibility variants in AF were systematically searched for in the ESP population. As illustrated by the last three columns in Tables 2, 3, 4 the vast majority of rare variants associated with AF were not present in the ESP population supporting that these variants are not random findings in original studies but indeed disease-causing or susceptibility mutations. If we make a(n) (arbitrary) cutoff point regarding prevalence of the variants in ESP at 0.5‰ of the total alleles corresponding to 1‰ of individuals (wary set) only p.(Ser422Leu) (KCNJ8), p.(Ser216Leu), p.(Leu461Val), p.(Arg481Trp), p.(Ser524Tyr), p.(Ala572Val), p.(Leu618Phe), p.(Arg1193Gln) and p.(Phe2004Leu) (SCN5A), p.(Ser64Arg) (NPPA), p.(Ala411Val) (GATA4) and p.(Gln76Glu) (GREM2) must be regarded as rare genetic variants less likely to be the major/monogenic cause of the disease. This is in contrast to four recently published articles concerning the prevalence in ESP of previously described mutations in genes involved in pathogenesis of long QT syndrome (LQTS), sudden infant death syndrome (SIDS), cardiomyopathy and BrS. Here the investigators found a very high prevalence of previously described mutations in the ESP population. These findings question the disease-causing role of some of these variants in LQTS, SIDS, cardiomyopathy and BrS.100, 101, 102, 103

Genetic overlap with other cardiac diseases

There is a large overlap between different genes involved in arrhythmic diseases such as LQTS, BrS, short QT syndrome (SQTS), SIDS, cardiomyopathy and AF. The majority of genes associated with AF have been associated with other arrhythmic diseases. LQTS has been associated with mutations in KCNQ1,104 KCNE1-3,104, 105 KCNH2,104 KCNJ2,104 and SCN5A.104 BrS has been associated with mutations in KCNE3,106 KCNE5,107 KCND3,108 KCNH2,109 SCN5A,110 SCN1Bb74 and SCN3B.111 Mutations in KCNQ1, KCNH2 and KCNJ2 have been associated with SQTS.104 SIDS has been associated with mutations in KCNQ1, KCNE1-2, KCNH2, KCNJ8, SCN5A, SCN1B, SCN3B and GJA1.101 Mutations in ABCC9,112 SCN5A,68 NPPA113 and LMNA102 have been associated with cardiomyopathy. Accordingly, nine genes associated with AF have not been associated with other arrhythmic diseases (KCNE4, KCNA5, SCN2B, NUP155, GJA5, GATA4, GATA6, NKX2-5 and GREM2). A conclusion could be that these genes are special for AF. Another explanation is simply that the genes have only been investigated in AF cohorts.

Patients with genetically proven SQTS or LQTS have a higher risk of early-onset AF than the general population.114, 115 In a study by Johnson et al,114 early-onset AF was observed in almost 2% of patients with genetically proven LQTS compared with the background prevalence of 0.1%. Interestingly, we recently found that both shortened and prolonged QTc interval durations are risk factors for incident AF, and that the association was strongest with respect to lone AF. Thus, the QTc interval does not simply seem to be a marker of cardiac disease but instead seems to be an inherent characteristic of an individual's cardiac electrophysiology. Thereby, indicating a link between AF and patients with extremes of QTc interval.116

Evidence for interaction between common and rare genetic variants

Although traditional linkage analysis and candidate gene approaches have revealed numerous suspected disease-causing mutations in familial AF, penetrance in these families is highly variable. Moreover, the transmission mode of other forms of AF, although studies suggest a high degree of heritability, remains unclear. This indicates that AF inheritance is complex and in many cases non-Mendelian.

A recent study by Ritchie et al117 provide strong evidence that common genetic variants act as modifiers of rare genetic variants associated with familial AF. They studied whether the two previously reported common polymorphism in the chromosome 4q25 region15 contribute to the variable penetrance of familial AF. DNA sequence analysis was performed for KCNQ1, KCNA5, NKX2-5, SCN5A and NPPA. They identified 11 families in which AF was present in ≥2 members and who also shared a mutation in one of the mentioned genes. Six families were found with rare variants in SCN5A, one with rare variants in NKX2.5, two with rare variants in NPPA, one with rare variants in KCNQ1 and one family with a rare variant in KCNA5. The penetrance of AF in probands carrying the putative mutation was low. However, the investigators found a significant interaction between common and rare genetic variants and onset of AF suggesting that addition of 4q25 genotypes helped predict, which carriers of the rare variants developed AF.

Another recent study by Mann et al57 showed epistatic effects of potassium channel variation on cardiac repolarization and AF risk. The major cardiac K+ channels were sequenced and 19 non-synonymous variants in 9 genes were found, 11 of them rare (6 of them novel). In all, 60 of the 80 AF probands had 2 or more variants. Individually, the variants had modest effect on potassium current but combinations of different variants showed both shortening end lengthening of APD suggesting a cumulative effect of ion channel variants both with regard to rare and common variants.

Olesen et al118 just recently added further evidence for an interaction between common and rare genetic variants. In a lone AF patient, a mutation in KCND3 was identified. Moreover, the patient was homozygous for the risk allele at both the ZFHX3 (rs2106261) and KCNN3 (rs13376333) loci, indicating that the patient was predisposed by common variants.

Genetic testing in AF

Ackerman et al119 stated the recommendations for genetic testing in channelopathies and cardiomyopathies in a Heart Rhythm Society/European Heart Rhythm Society expert consensus document. Despite the high number of genes related to AF, the authors stated that genetic testing is not indicated for AF because none of the known disease-associated genes have been shown to account for ≥5% of the disease. Moreover, although several SNPs have been associated with AF, little information links these specific genetic variants to distinct clinical outcomes for AF. However, a newly published article by Everett et al120 added new knowledge regarding the link between SNPs and clinical outcome. The authors derived and validated a novel risk prediction model from 32 possible predictors in a cohort of 20 822 women without cardiovascular disease at baseline. A genetic risk score was created, which comprised the nine loci discussed in the section ‘The role of common genetic variants'. The addition of genetic score to the AF risk algorithm model improved the c-index. This suggests that common variants in future could be used for risk stratification. Furthermore, genetic testing in AF could be an opportunity in near future with the implementation of NGS where whole genomes can be sequenced in few days.

Specific variants detected in patients, could potentially predict whether or not the patient will have a beneficial response to a specific drug. Thereby, genetic information may be used in personalized medicine in the future.

Summary

In recent years, the evidence concerning the genetic basis of AF has been rapidly increasing. Many monogenic mutations or rare variants have been revealed by candidate gene approaches. Although useful in understanding the pathophysiology of AF, these mutations or rare variants are limited in explaining the heritability of AF because they only account for sporadic or familial cases of AF. GWAS are powerful in identifying new loci associated with an increased risk for development of AF. In the last 5 years, nine non-coding SNPs have been associated with increased risk of AF. These SNPs are believed to be signals for the causative genes. The genes in closest proximity to these SNPs have therefore been investigated and given new and valuable knowledge. However, the exact biological pathway between these non-coding SNPs and the emergence of AF still remains unsolved.

The new knowledge from the exome project and the implementation of NGS will hopefully make it possible to gain further insight to our understanding of AF.

Acknowledgments

This study was funded by grants from the John and Birthe Meyer Foundation, the Arvid Nilsson Foundation, the Director Ib Henriksens Foundation, the Villadsen Family Foundation and the stock broker Henry Hansen and wife Karla Hansen, born Westergaard.

The authors declare no conflict of interest.

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