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.