Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes

Background Adverse pregnancy outcomes (APO) may unmask a woman’s underlying risk for coronary heart disease (CHD). To test this, we estimated associations between genetically predicted liability for CHD and risk of APOs in mothers and their male partners. We hypothesized that associations would be found for women, but not their partners (negative controls). Methods We studied up to 83,969 women (and up to 55,568 male partners) participating in the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and information on history of any APO in their pregnancies (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants ( p -value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis. Results One standard deviation increase in the GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96 to 1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98 to 1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners’ GRS and restricting analyses to stable couples. Associations for miscarriage, gestational diabetes, and spontaneous preterm birth were close to the null. In male partners, there was weak evidence of an association with spontaneous preterm birth (OR 1.02 [0.99 to 1.05]), but not with other APOs. Conclusions Hypertensive disorders of pregnancy, small for gestational age and stillbirth unmask women with a genetically predicted existing propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth needs further exploration. ### Competing Interest Statement O.A.A. is a consultant for cortechs.ai and has received speaker's honoraria from Sunovion, Janssen, and Lundbeck. D.A.L. receives (or has received in the last 10 years) research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. The rest of the authors no conflict of interest. ### Funding Statement This project received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement number 947684, 964874, and 101021566). This work was also supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700, and partly funded by the Research Council of Norway, project "Women's fertility - an essential component of health and well-being" (project number 320656), and project number 223273. Open Access funding was provided by the Norwegian Institute of Public Health. P.R.N. was supported by the European Research Council (grant agreement No 293574). E.C. and A.Havdahl were supported by the Research Council of Norway (274611) and the South-Eastern Norway Regional Health Authority (project numbers 2020022, 2021045). B.B. and B.O.A. work at the K.G. Jebsen Center for Genetic Epidemiology, which is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norway. D.A.L. and A.F. are affiliated with a unit that receives funding from the UK Medical Research Council (MC-UU-00032/05). D.A.L. was supported by the British Heart Foundation (CH/F/20/90003 and AA/18/1/34219) and the European Research Council (grant agreement No 101021566). The funders had no role in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. ### 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: Both MoBa and HUNT follow the Declaration of Helsinki for Medical Research on human subjects. MoBa is currently regulated by the Norwegian Health Registry Act and its data collection is approved by the Norwegian Data Protection Authority. HUNT was authorized by the Regional Committee for Medical and Health Research (Health Region IV, Norway). Participants provided a written informed consent before joining the cohorts. This project was particularly approved by the Regional Committee for Medical and Health Research Ethics of South/East Norway (references: 2017/1362 and 78545). 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 consent given by the MoBa and HUNT participants does not allow for storage of individual data in repositories or journals. Researchers who want to access MoBa datasets for replication should apply by sending an e-mail to datatilgang@fhi.no. This procedure requires approval from the Regional Committee for Medical and Health Research Ethics in Norway and an agreement with MoBa. Data from the HUNT Study used for research are available upon request to the HUNT Data Access Committee (hunt@medisin.ntnu.no) to research groups who meet the data availability requirements described in http://www.ntnu.edu/hunt/data. Source data of the GWAS on CHD are available in the Online Table VI of the article of Van Der Harst P et al., Circ Res, 2018, available in the Supplemental Materials (https://www.ahajournals.org/doi/suppl/10.1161/CIRCRESAHA.117.312086), as well as in the IEU Open GWAS website (code: ebi-a-GCST005195). * APO : adverse pregnancy outcome CHD : coronary heart disease CI : confidence interval GD : gestational diabetes GRS : genetic risk score GWAS : genome-wide association study HDP : hypertensive disorders of pregnancy HUNT : Trøndelag Health Study LGA : large for gestational age MBRN : Medical Birth Registry of Norway MoBa : Mother, Father, and Child Cohort Study OR : odds ratio SGA : small for gestational age SD : standard deviation sPTB : spontaneous preterm birth