Sex-specific genetic determinants of right ventricular structure and function

Background While sex differences in right heart phenotypes have been observed, the molecular drivers remain unknown. We used common genetic variation to provide biological insights into sex differences in the structure and function of the right ventricle (RV). Methods RV phenotypes were obtained from cardiac magnetic resonance imaging in 18,156 women and 16,171 men from the UK Biobank, based on a deep-learning approach, including end-diastolic, end-systolic, and stroke volumes, as well as ejection fraction. Observational analyses and sex-stratified genome-wide association studies were performed. Candidate female-specific loci were evaluated against invasively measured hemodynamics 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. Results Sex was associated with differences in RV volumes and ejection fraction in models adjusting for left heart counterparts and lung function. Six genome-wide significant loci (13%) revealed heterogeneity of allelic effects between women and men. These included two sex-specific candidate loci present in women only; namely, a locus for RV ejection fraction in BMPR1A and a locus for RV end-systolic volume near DMRT2 . Epigenetic data indicate that variation at the BMPR1A locus likely alters transcriptional regulation in RV tissue. In female patients with PAH, a variant located in the promoter of BMPR1A was significantly associated with cardiac index (effect size 0.16 l/min/m 2 ), despite similar RV afterload among genotypic groups. Conclusions We report sex-specific genetic loci for RV structure and function. BMPR1A 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. Further studies are needed to explore the underlying biological pathways.