Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes: a cohort study

Álvaro Hernáez, Karoline H Skåra, Christian M Page, Vera Mitter, M Hernández, Per M Magnus, PR Njølstad, Ole Andreas Andreasen, Elizabeth C Corfield, Karoline Alexandra Havdahl, Øyvind Næss, Ben Brumpton, Bjørn Olav Åsvold, Debbie A Lawlor, Abigail Fraser, Maria Christine Magnus

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Background
Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman’s underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls).

Methods
We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967–2019) in the Medical Birth Registry of Norway (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 higher 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 0.96–1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98–1.11) 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 other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99–1.05), but not with other APOs.

Conclusions
Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.
Original languageEnglish
Article number35
JournalBMC Medicine
Volume22
Issue number1
DOIs
Publication statusPublished - 25 Jan 2024

Bibliographical note

Funding Information:
We thank the Norwegian Institute of Public Health for generating high-quality genomic data in the MoBa study. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Health Authority, and Stiftelsen Kristian Gerhard Jebsen. We further thank the Center for Diabetes Research (University of Bergen) for providing genotype information and performing quality control and imputation of the data, in the context of research projects funded by the European Research Council Advanced Grant SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authority.

Funding Information:
The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The HUNT Study is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research and Innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. We are grateful to all the participants in Norway who take part in the MoBa and HUNT studies, those who contributed to the recruitment, and the infrastructure surrounding both cohorts.

Funding Information:
The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The HUNT Study is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research and Innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. We are grateful to all the participants in Norway who take part in the MoBa and HUNT studies, those who contributed to the recruitment, and the infrastructure surrounding both cohorts. We thank the Norwegian Institute of Public Health for generating high-quality genomic data in the MoBa study. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Health Authority, and Stiftelsen Kristian Gerhard Jebsen. We further thank the Center for Diabetes Research (University of Bergen) for providing genotype information and performing quality control and imputation of the data, in the context of research projects funded by the European Research Council Advanced Grant SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authority. This work was developed on the TSD (Tjeneste for Sensitive Data) online facilities, owned by the University of Oslo, which are operated and developed by the TSD service group at the IT-Department in University of Oslo (tsd-drift@usit.uio.no). This paper does not necessarily reflect the position or policy of the Norwegian Research Council.

Funding Information:
Open access funding provided by Norwegian Institute of Public Health (FHI). 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.

Publisher Copyright:
© 2023, The Author(s).

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