Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and offspring outcomes. Current tools for prediction, prevention, and treatment are limited. In discovery analysis, we tested the association of maternal DNA sequence variants with preeclampsia in 17,150 cases and 451,241 controls and with gestational hypertension in 8,961 cases and 184,925 controls using multi-ancestry meta-analysis. We identified 12 independent loci associated with preeclampsia/eclampsia, 7 of which are novel (including MTHFR-CLCN6, WNT3A, PGR, FLT1, and RGL3), and 7 loci associated with gestational hypertension. 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 datasets, independent of first-trimester risk markers. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and advance pregnancy risk stratification.

M.C.H. reports consulting fees from CRISPR Therapeutics, advisory board service for Miga Health, and grant support from Genentech, all unrelated to this work. K.J.G. has served as a consultant for BillionToOne, Aetion, and Roche for projects unrelated to this work. R.S. is a co-founder of Magnet Biomedicine, unrelated to this work. R.D. reports receiving grants from AstraZeneca, grants and nonfinancial support from Goldfinch Bio, being a scientific co-founder, consultant, and equity holder for Pensieve Health (pending), and being a consultant for Variant Bio, all unrelated to this work. P.N. reports grant support from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, spousal employment and equity at Vertex, consulting income from Apple, AstraZeneca, Novartis, Genentech / Roche, Blackstone Life Sciences, Foresite Labs, and TenSixteen Bio, and is a scientific advisor board member and shareholder of TenSixteen Bio and geneXwell, all unrelated to this work.

This work was supported by grants from the American Heart Association 940166 (M.C.H.), 979465 (M.C.H.); the Korea Health Industry Development Institute HI19C1330 (S.M.J.C.); Harvard Catalyst Medical Research Investigator Training Program (A.P.P.); National Human Genome Research Institute U01HG011719 (A.P.P. and P.N.); the Belgian American Educational Foundation (A.S.); the U.S. National Institute of General Medical Sciences R35GM147197 (R.F.G.), R35GM124836 (R.D.); the U.S. National Heart Lung and Blood Institute K08HL146963 (K.J.G.), R01HL139865 (R.D.), R01HL155915 (R.D.), DP2HL152423 (R.M.G.), U01HL166060 (R.M.G.), R03HL148483 (R.M.G.), R01HL142711 (P.N.), R01HL127564 (P.N.), R01HL148050 (P.N.), R01HL151283 (P.N.), R01HL148565 (P.N.), R01HL135242 (P.N.), R01HL151152 (P.N.); National Institute of Diabetes and Digestive and Kidney Diseases R01DK125782 (P.N.); National Institute of Child Health and Human Development R01HD101246 (D.M.H.); Preeclampsia Foundation (K.J.G., R.S.); Fondation Leducq TNE-18CVD04 (P.N.); and the Massachusetts General Hospital Paul and Phyllis Fireman Endowed Chair in Vascular Medicine (P.N.).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Estonian Committee on Bioethics gave ethical approval for the work conducted in the Estonian Biobank. The South East Research Ethics Committee gave ethical approval for the work conducted in Genes & Health. The University of Michigan Medical School Institutional Review Board gave ethical approval for the work conducted in the Michigan Genomics Initiative. The Mass General Brigham Institutional Review Broad gave ethical approval for the work conducted in the Mass General Brigham Biobank and for secondary analyses of UK Biobank data. The Regional Committee for Ethics in Medical Research, Norway (2018/2488) gave ethical approval for the work conducted in HUNT.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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GWAS summary statistics for preeclampsia/eclampsia and gestational hypertension and corresponding genome-wide polygenic scores will be made publicly available upon publication. Summary statistics used in this meta-analysis are publicly available for FinnGen r6 (https://www.finngen.fi/en/access_results) and for BioBank Japan (https://pheweb.jp/pheno/PreEclampsia). Summary statistics from the InterPregGen consortium are available at https://ega-archive.org. Placental transcriptome data are publicly available at https://www.obgyn.cam.ac.uk/placentome/.