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/m2), 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The UK Biobank was established through core funding by the Wellcome Trust medical charity, the Medical Research Council, the Department of Health, the Scottish Government, and the Northwest Regional Development Agency. It has also had funding from the Welsh Government, British Heart Foundation, Cancer Research UK and Diabetes UK. This work was supported by the NIHR BioResource which supports the UK National Cohort of Idiopathic and Heritable PAH; the British Heart Foundation (BHF SP/12/12/29836) and the UK Medical Research Council (MR/K020919/1). This work was supported in part by the British Heart Foundation Centre for Research Excellence award RE/18/4/34215. Christopher J. Rhodes is supported by BHF Basic Science Research fellowship (FS/SBSRF/21/31025). Khodr Tello is supported by a German Research Foundation Collaborative Research Centre award (SFB1213/1). Arunashis Sau is supported by a British Heart Foundation clinical research training fellowship (FS/CRTF/21/24183). Ewa Sieliwonczyk is supported by a European Joint Programme on Rare Diseases research mobility fellowships (European Reference Networks). Fu Siong Ng is supported by the British Heart Foundation (RG/F/22/110078 and RE/18/4/34215) and the National Institute for Health Research Imperial Biomedical Research Centre. The funder had no role in study design, data collection, data analysis, data interpretation, or writing of this article. The views expressed are those of the authors. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank: The study protocol was approved by the Northwest Research Ethics Committee under reference number 11/NW/0382. All participants were informed and gave written informed consent. NIHR Rare Disease Study: All enrolled patients provided written informed consent from their respective institutions. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The raw imaging data, genotype data and non-imaging participant characteristics are available from UK Biobank via a standard application procedure at http://www.ukbiobank.ac.uk/. Summary GWAS statistics will be made available upon publication. Further web links for the publicly available datasets used in the study are as follows: PhenoScanner (http://www.phenoscanner.medschl.cam.ac.uk), GTEx (https://gtexportal.org), Ensembl VEP (https://www.ensembl.org/info/docs/tools/vep), ENCODE (https://www.encodeproject.org), and NCBI GEO (https://www.ncbi.nlm.nih.gov/geo/). All other data are contained in the article file and its supplementary information or are available upon request.