Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Abstract

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.

Fig. 1. Manhattan plots of genome-wide association results from the preeclampsia meta-analyses.

P-values (−log₁₀) from the meta-analysis are plotted against their respective positions on each chromosome. a Offspring of preeclamptic pregnancies from Europe and Central Asia (6775 cases and 375,372 controls). b Preeclamptic women from Europe and Central Asia (9515 cases and 157,719 controls).

Fig. 2. Genetic correlation between maternal preeclampsia and selected traits.

Genetic correlation between pairs of traits using the cross-trait LD-score regression method in the European maternal preeclampsia data sets and the summary statistics from deCODE and UK Biobank data sets for each secondary trait. On one hand, we calculated the genetic correlation between preeclampsia meta-analysis of GOPEC, ALSPAC, and MoBa data, and deCODE GWAS summary statistic for each secondary trait, and on the other hand between preeclampsia meta-analysis of deCODE, SSI, and FINRISK data, and UK Biobank GWAS summary statistic for each secondary trait. The P-values and genetic correlation estimates presented are the meta-analysis of the two independent tests, with the exception of birth weight of first child where the results only include the preeclampsia meta-analysis excluding UK data sets and the UK biobank data on birth weight of the first child. The height of the bars indicates the genetic correlation, blue bars indicate a positive correlation, red bars indicate a negative correlation. Error bars indicate standard error. Red asterisks indicate results that are significant after accounting for the 12 traits tested. Significance threshold: P = 0.05/12 = 0.0042. Details of the results presented in the figure are reported in Supplementary Table 11.

Fig. 3. Polygenic risk score analysis using PRS for hypertension.

PRS effect estimates were based on GWAS analysis of the UKBB hypertension data set. The top panel shows association between the HT-PRS and hypertension (females only), gestational hypertension and preeclampsia in genotyped subjects from the deCODE cohort. The control group comprises females that are not on any of the case lists (hypertension-free controls). For other studies, the association analysis used the preeclampsia cases and controls that were included in the respective maternal GWAS analyses. Effect reported as log-odds corresponds to the increase in risk of the respective trait for one standard deviation of the hypertension risk score. 95% CI: 95% confidence interval. P-values are obtained from logistic regression of case status on individuals’ polygenic risk score, adjusted for covariates (see “Methods” section). All P-values are two-sided. R² denotes the explained variance.