Preeclampsia prediction with maternal and paternal polygenic risk scores: the TMM BirThree Cohort Study

Background: Genomic information from pregnant women and their husbands may provide effective biomarkers for preeclampsia. This study investigated how parental polygenic risk scores (PRSs) for blood pressure (BP) and preeclampsia are associated with preeclampsia onset and evaluated predictive performances of PRSs with clinical predictive variables. Methods: In the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study, participants were genotyped using either Affymetrix Axiom Japonica Array v2 (further divided into two cohorts?the PRS training cohort and the internal-validation cohort?at a ratio of 1:2) or Japonica Array NEO (external-validation cohort). PRSs were calculated for systolic BP (SBP), diastolic BP (DBP), and preeclampsia. Associations between PRSs and preeclampsia, including preeclampsia superimposed on chronic hypertension, were examined using logistic regression analysis; prediction models were developed using a competing-risks approach with clinical predictive variables and PRSs. Results: In total, 19,836 participants were included. Hyperparameters for PRS calculation were optimized for 3,384 participants in the training cohort. In internal- and external-validation cohorts, 357 of 6,768 (5.3%) and 269 of 9,684 (2.8%) participants developed preeclampsia, respectively. Preeclampsia onset was significantly associated with maternal PRSs for SBP and DBP in internal- and external-validation cohorts and with paternal PRSs for SBP and DBP only in the external-validation cohort. Maternal PRSs for DBP calculated using ?LDpred2? most improved prediction models. Maternal PRSs for DBP provided additional predictive information on clinical predictive variables. Paternal PRSs for DBP improved prediction models in the internal-validation cohort. Conclusions: Parental PRS, along with clinical predictive variables, is potentially useful for predicting preeclampsia. ### Competing Interest Statement KM is an employee of the Ministry of Education, Culture, Sports, Science and Technology, Japan. ### Funding Statement This work was supported by the Japan Agency for Medical Research and Development (AMED), Japan (Grant Nos. JP19gk0110039, JP17km0105001, JP21tm0124005, and JP21tm0424601) and JSPS KAKENHI (Grant No. JP21K10438). ### 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: Ethical approval was obtained from the Ethics Committee of the Tohoku Medical Megabank Organization (2023-4-025), and informed consent for research participation was obtained from all participants. 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 Individual cohort and genotyping data are available upon request after the approval of the Ethical Committee and the Materials and Information Distribution Review Committee of Tohoku Medical Megabank Organization.