Constellation of Risk Variants
The polygenic risk score did not predict appendage morphology but the
PITX2 risk allele with the largest effect size was associated with
non-CW morphology. Similarly, prior studies have shown the RS2200733
4q25 variant alone does not stratify CTI patients who will go on to
develop AF28, yet in this study a polygenic risk score
was able to discriminate this group. These findings highlights the need
for much broader clinical genotyping and much more granular phenotyping
to fully understand the relationships between genetics and disease.
Large-scale GWAS have now identified more than 100 loci associated with
AF29-31. Despite the number, these loci explain only a
modest proportion of the heritability32, suggesting
that more AF-related genetic loci remain to be identified. As the number
of association loci increases, so effect sizes diminish and competing
functions are more likely to obscure some orthogonal non AF phenotypic
associations. For example, some variants might mediate arrhythmogenesis
via a similar pathway to PITX2, yet others might act through unrelated
but synergistic pathways6. As with much of medicine,
the balance between personalization of care and grouping of data must be
carefully considered.