Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death¹. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility². Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets^3,4. 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 preeclampsia⁵. 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.

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 atZNF831/20q13 andFTO/16q12. These are previously established variants for blood pressure (BP) and theFTOvariant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants atMECOM/3q26,FGF5/4q21 andSH2B3/12q24 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.

Elucidating the genetic architecture of preeclampsia is a major goal in obstetric medicine. We have performed a genome-wide association study (GWAS) for preeclampsia in unrelated Australian individuals of Caucasian ancestry using the Illumina OmniExpress-12 BeadChip to successfully genotype 648,175 SNPs in 538 preeclampsia cases and 540 normal pregnancy controls. Two SNP associations (rs7579169, p = 3.58×10⁻⁷, OR = 1.57; rs12711941, p = 4.26×10⁻⁷, OR = 1.56) satisfied our genome-wide significance threshold (modified Bonferroni p<5.11×10⁻⁷). These SNPs reside in an intergenic region less than 15 kb downstream from the 3′ terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. They are in linkage disequilibrium (LD) with each other (r² = 0.92), but not (r²0.92). We attempted to provide evidence of a putative regulatory role for these SNPs using bioinformatic analyses and found that they all reside within regions of low sequence conservation and/or low complexity, suggesting functional importance is low. We also explored the mRNA expression in decidua of genes ±500 kb of INHBB and found a nominally significant correlation between a transcript encoded by the EPB41L5 gene, ∼250 kb centromeric to INHBB, and preeclampsia (p = 0.03). We were unable to replicate the associations shown by the significant GWAS SNPs in case-control cohorts from Norway and Finland, leading us to conclude that it is more likely that these SNPs are in LD with as yet unidentified causal variant(s).

Background: Preeclampsia is a severe pregnancy disorder often complicated by reduced fetal growth or preterm delivery and is associated with long‐term maternal morbidity and mortality. We aimed to assess the association between preeclampsia phenotypes and risk of subsequent coronary heart disease and maternal cardiovascular mortality. Methods and Results: Women aged 16 to 49 years who gave birth during 1980–2002 and registered in the Medical Birth Registry of Norway were followed prospectively (1–29 years) for an incident major coronary event and mortality through linkage with the Cardiovascular Disease in Norway 1994–2009 ( CVDNOR ) project and the Norwegian Cause of Death Registry. Preeclampsia was subdivided based on the presence of a child born small for gestational age or preterm delivery. Among 506 350 women with 1 to 5 singleton births, there were 1275 (0.3%) occurrences of major coronary event, 468 (0.1%) cardiovascular deaths, and 5411 (1.1%) deaths overall. Compared with women without preeclampsia, the hazard ratio (95% CI) for major coronary event was 2.1 (1.73–2.65) after preeclampsia alone, 3.3 (2.37–4.57) after preeclampsia in combination with small for gestational age, and 5.4 (3.74–7.74) after preeclampsia in combination with preterm delivery. Analyses distinguishing women with 1 (n=61 352) or >1 (n=281 069) lifetime pregnancy and analyses with cardiovascular mortality as outcome followed the same pattern. Conclusions: The occurrence of major coronary events was increased among women with preeclampsia and highest for preeclampsia combined with a child born small for gestational age and/or preterm delivery.

Pre‐eclampsia is associated with increased levels of cholesterol and uric acid and an inflamed placenta expressing danger‐sensing pattern recognition receptors (PRRs). Crystalline cholesterol and uric acid activate the PRR Nod‐like receptor protein (NLRP)3 inflammasome to release interleukin (IL)‐1β and result in vigorous inflammation. We aimed to characterize crystal‐induced NLRP3 activation in placental inflammation and examine its role in pre‐eclampsia. We confirmed that serum total cholesterol and uric acid were elevated in pre‐eclamptic compared to healthy pregnancies and correlated positively to high sensitivity C‐reactive protein (hsCRP) and the pre‐eclampsia marker soluble fms‐like tyrosine kinase‐1 (sFlt‐1). The NLRP3 inflammasome pathway components (NLRP3, caspase‐1, IL‐1β) and priming factors [complement component 5a (C5a) and terminal complement complex (TCC)] were co‐expressed by the syncytiotrophoblast layer which covers the placental surface and interacts with maternal blood. The expression of IL‐1β and TCC was increased significantly and C5a‐positive regions in the syncytiotrophoblast layer appeared more frequent in pre‐eclamptic compared to normal pregnancies. In‐vitro activation of placental explants and trophoblasts confirmed NLRP3 inflammasome pathway functionality by complement‐primed crystal‐induced release of IL‐1β. This study confirms crystal‐induced NLRP3 inflammasome activation located at the syncytiotrophoblast layer as a mechanism of placental inflammation and suggests contribution of enhanced NLRP3 activation to the harmful placental inflammation in pre‐eclampsia.

Objective To test the hypothesis that pre-eclampsia is a risk factor for cerebral palsy mediated through preterm birth and being born small for gestational age. Design Population based cohort study. Setting Clinical data from the Norwegian Cerebral Palsy Registry were linked with perinatal data prospectively recorded by the Medical Birth Registry of Norway. Participants All singleton babies who survived the neonatal period during 1996-2006 (849 children with cerebral palsy and 616 658 control children). Main outcome measures Cerebral palsy and cerebral palsy subtypes. Results Children exposed to pre-eclampsia had an excess risk of cerebral palsy (unadjusted odds ratio 2.5, 95% confidence interval 2.0 to 3.2) compared with unexposed children. Among children born at term (≥37 weeks), exposure to pre-eclampsia was not associated with an excess risk of cerebral palsy in babies not born small for gestational age (1.2, 0.7 to 2.0), whereas children exposed to pre-eclampsia and born small for gestational age had a significantly increased risk of cerebral palsy (3.2, 1.5 to 6.7). Non-small for gestational age babies born very preterm (<32 weeks) and exposed to pre-eclampsia had a reduced risk of cerebral palsy compared with unexposed children born at the same gestational age (0.5, 0.3 to 0.8), although the risk was not statistically significantly reduced among children exposed to pre-eclampsia and born small for gestational age (0.7, 0.4 to 1.3). Exposure to pre-eclampsia was not associated with a specific cerebral palsy subtype. Conclusions Exposure to pre-eclampsia was associated with an increased risk of cerebral palsy, and this association was mediated through the children being born preterm or small for gestational age, or both. Among children born at term, pre-eclampsia was a risk factor for cerebral palsy only when the children were small for gestational age.