Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and child outcomes. Current tools for prediction, prevention and treatment are limited. Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are new (for example, MTHFR–CLCN6, WNT3A, NPR3, PGR and RGL3), including two loci (PLCE1 and FURIN) identified in the multitrait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external cohorts, independent of clinical risk factors, and reclassified eligibility for low-dose aspirin to prevent preeclampsia. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and have the potential to advance pregnancy risk stratification.

先兆子痫和妊娠高血压是常见的妊娠并发症，与不良母婴结局相关。目前的预测、预防和治疗工具有限。在这里，我们使用多祖先荟萃分析，在发现和随访队列中测试了 20,064 例病例和 703,117 名对照个体中母体 DNA 序列变异与先兆子痫的关联，以及 11,027 例病例和 412,788 名对照个体中母体 DNA 序列变异与妊娠高血压的关联。我们总共鉴定了 18 个与先兆子痫/子痫和/或妊娠高血压相关的独立基因座，其中 12 个是新的（例如，MTHFR – CLCN6 、 WNT3A 、 NPR3 、 PGR和RGL3 ），包括在多性状分析。已确定的位点强调了利钠肽信号传导、血管生成、肾小球功能、滋养层发育和免疫失调的作用。我们得出了全基因组多基因风险评分，预测外部队列中的先兆子痫/子痫和妊娠高血压，与临床危险因素无关，并重新分类了低剂量阿司匹林预防先兆子痫的资格。总的来说，这些发现提供了对妊娠高血压疾病的机制见解，并有可能推进妊娠风险分层。