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.49 One such gene that has garnered
significant attention is SCN5A , which encodes the sodium channel
that controls inward sodium current as part of atrial
depolarization.50 SCN5A mutations have been
described in long QT syndrome type 3, Brugada
syndrome51, familial dilated cardiomyopathy
(DCM).52,53 Mutations in 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.54,55
Importantly, there is a growing understanding of the overlap between AF
and genetic DCM. The most prominent example is that of TTNcardiomyopathy. TTN encodes the largest human protein, and
truncating variants in TTN (TTNtv ) have previously been
implicated in 25% of familial cases of DCM56 and
linked to increased risk of ventricular arrhythmias.57Patients with TTN DCM are known to have high rates of
AF58 and be more likely to develop persistent
AF.57 TTNtv also appear to lead to increased
risk of AF59, even when controlling for cardiomyopathy
status.60 In one population of familial AF,TTNtv were associated with AF onset at median age of 26, and all
variants were in the cardiac isoforms of TTN . Of interest, in
this analysis, 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.61 LOF variants in TTN are
more common among patients with early-onset AF compared to healthy
controls62, with a higher proportion of variants seen
in younger patients at time of AF diagnosis.63Additionally, when compared to all patients with AF, early-onset AFTTNtv 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.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.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.66Another 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).59 This finding was replicated in the
Framingham cohort, where clinical risk factors were shown to further
modify AF risk within individual PRS subgroups.67Finally, a higher PRS is also associated with higher risk of AF inTTN LOF variant carriers.68 However, there are
no current models combining SNPs and clinical risk factors to predict
long-term outcomes of patients with AF.