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

Abstract

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 Trondelag 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 x 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.