Beyond the Canonical Loci of Brugada Syndrome, Takotsubo Cardiomyopathy and Primary Pulmonary Arterial Hypertension

Background: The rare cardiovascular diseases of Brugada Syndrome, takotsubo Cardiomyopathy, and primary pulmonary arterial hypertension remain comparatively under-investigated despite their substantial morbidity and mortality. While common cardiovascular diseases have benefited from extensive genomic and therapeutic research, the molecular mechanisms underlying rarer cardiovascular conditions remain incompletely understood. This study aimed to investigate the genetic architecture and potential causal protein mediators of these rare cardiovascular diseases using integrated genomic and proteomic analyses. Methods: Genome-wide association analyses were performed within the UK Biobank cohort for Brugada syndrome, takotsubo cardiomyopathy, and pulmonary arterial hypertension. Significant loci were identified following standard quality-control procedures and annotated using publicly available genomic databases. Protein-protein interaction networks were generated using STRING to investigate known and predicted biological relationships among identified genes and to explore potential shared disease mechanisms. Proteomic Mendelian randomisation analyses were subsequently conducted using protein quantitative trait loci (pQTLs) and Generalised Summary Mendelian Randomisation (GSMR) to evaluate whether genetically predicted circulating protein levels were associated with disease risk. Results: Distinct genetic architectures were observed across phenotypes. Brugada syndrome demonstrated a concentrated association signal within the THSD7B locus alongside a variant in TRPC4. Takotsubo cardiomyopathy demonstrated associations involving ANKRD31 and PREX1, while primary pulmonary arterial hypertension identified loci involving ANO10 and SHF. Several significant variants could not be mapped to annotated genes, particularly within takotsubo cardiomyopathy, suggesting potential contributions from non-coding or regulatory genomic regions. Interaction network analyses identified biologically plausible relationships between identified loci and established cardiovascular pathways. Evaluation of circulating proteins as potential mediators of disease risk identified limited evidence for causal effects, although LPA emerged as a candidate protein associated with takotsubo cardiomyopathy and other ill-defined heart diseases. Conclusions: These findings demonstrate substantial genetic heterogeneity across Brugada syndrome, primary pulmonary arterial hypertension, and takotsubo cardiomyopathy whilst highlighting shared biological themes involving electrophysiological regulation, calcium signalling, inflammation, and tissue remodelling. The integration of genomic association analyses, interaction-network approaches, and proteomic causal inference provides additional insight into the molecular pathways underlying these three cardiovascular diseases and may help prioritise targets for future functional investigation.