Sex-Specific Genetic Determinants of Right Ventricular Structure and Function

<b>Rationale:</b> Although sex differences in right heart phenotypes have been observed, the molecular drivers remain unknown. <b>Objectives:</b> To provide biological insights into sex differences in the structure and function of the right ventricle (RV) using common genetic variation. <b>Methods:</b> RV phenotypes were obtained from cardiac magnetic resonance imaging in 18,156 women and 16,171 men from the UK Biobank. Observational analyses and sex-stratified genome-wide association studies were performed. Candidate female-specific loci were evaluated against invasively measured cardiac performance in 479 female patients with idiopathic or heritable pulmonary arterial hypertension (PAH), recruited to the UK National Institute for Health Research BioResource Rare Diseases study. <b>Measurements and Main Results:</b> Sex was associated with differences in RV volumes and ejection fraction in models adjusting for left heart counterparts, blood pressure, lung function, and sex hormone concentrations. Six genome-wide significant loci (13%) revealed heterogeneity of allelic effects between women and men and significant sex-by-genotype interaction. These included two sex-specific candidate loci present in women only: a locus for RV ejection fraction in <i>BMPR1A</i> (bone morphogenetic protein receptor type 1A) and a locus for RV end-systolic volume near <i>DMRT2</i> (doublesex and mab-3 related transcription factor 2). Epigenetic data in RV tissue indicate that variation at the <i>BMPR1A</i> locus likely alters transcriptional regulation. In female patients with PAH, a variant located in the promoter of <i>BMPR1A</i> was significantly associated with cardiac index (effect size, 0.16 L/min/m²), despite similar RV afterload. <b>Conclusions:</b> <i>BMPR1A</i> has emerged as a biologically plausible candidate gene for female-specific genetic determination of RV function, showing associations with cardiac performance under chronically increased afterload in female patients with PAH.