Advances in cardiogenetics From large-scale genomics to clinical considerations

Over the past few years, large international consortia and biobank studies have fueled a revolutionary era of genomic medicine. As sequencing datasets have reached unprecedented size, rare variant association studies have demonstrated utility in identifying known and novel protein-coding genes relevant to common cardiovascular disease. An archetypal example is represented in atrial fibrillation, for which study of over 52000 cases identified several genes harboring rare variants predisposing to the arrhythmia. At the same time, consortium efforts have assembled large-scale genome-wide data to study common genetic variation in rare cardiovascular disorders. Exemplified by a GWAS in over 9000 cases of dilated cardiomyopathy, rare disease GWAS may uncover dozens of relevant loci and offer hints towards causal cellular mechanisms and risk factors. In terms of genetic architecture, broadly, these data show that common genetic variation may contribute substantially to rare disease, while rare genetic variants may pin-point specific mechanisms and subtypes of common disease. These large genomic studies have, furthermore, yielded insights of potential clinical relevance. Polygenic risk scores constructed from GWAS stratify risk of cardiomyopathy on top of pathogenic rare variants and clinical factors, offering promise for stratification in at-risk groups. In turn, rare pathogenic variants are common in early-onset forms of atrial fibrillation, suggesting that genetic testing might inform prognosis and management. These data illustrate how large-scale genomics has expanded our understanding of cardiovascular disease and suggest that a world of broad genomic medicine is approaching. Despite substantial ongoing progress, however, Eurocentric bias continues to plague genomic datasets and knowledge. Ongoing efforts towards improved diversity are showing promise, but more non-European data is required for equitable clinical application. Furthermore, additional prospective cohort studies, clinical trials, and cost-benefit studies may be required to show utility of novel genomic medicine applications, and more sophisticated bioinformatic infrastructures will likely be needed in the future. From a mechanistic perspective, large-scale functional studies will be needed to translate the many identified molecular targets into potential therapeutic strategies. Overall, this thesis demonstrates significant advancements in genomic association testing and our understanding of genetic architecture, emphasizing the potential of genomic medicine to reduce the burden of cardiovascular disease.