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.
Subject(s)
Genetic Predisposition to Disease , Hypertension, Pregnancy-Induced/genetics , Multifactorial Inheritance , Pre-Eclampsia/genetics , Adaptor Proteins, Signal Transducing/genetics , Adult , Aged , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics , Asia, Central/epidemiology , Blood Pressure/genetics , Case-Control Studies , Datasets as Topic , Europe/epidemiology , Female , Fibroblast Growth Factor 5/genetics , Genetic Loci/genetics , Genome-Wide Association Study , Humans , Hypertension, Pregnancy-Induced/epidemiology , MDS1 and EVI1 Complex Locus Protein/genetics , Middle Aged , Pre-Eclampsia/epidemiology , Pregnancy , Prospective StudiesABSTRACT
Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.