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

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.

Keywords: Adverse pregnancy outcomes; Coronary heart disease; HUNT; MoBa; Parental genetic liability to CHD.

Fig. 1

Flow chart

Fig. 2

Associations between one SD higher maternal GRS for CHD and risk of APO and between one SD higher paternal GRS and risk of APO in female partners. Main analyses (pooled analyses from MoBa and HUNT participants) were conducted in 75,210 women for miscarriage, 83,900 for stillbirth, 83,114 for HDP, 83,900 for GD, 66,110 for SGA, 69,789 for LGA, and 83,522 for sPTB. Regarding men, APOs were detected in their female partners, and analyses were conducted in 51,156 individuals for miscarriage, 55,790 for stillbirth, 55,273 for HDP, 55,790 for GD, 43,967 for SGA, 46,104 for LGA, and 55,536 for sPTB. Sample sizes of additional analyses are described in Supplementary Table 3, being smallest for the analyses in the subgroup with genetic data on both parents