Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy
Jaakko Tyrmi, Tea Kaartokallio, A. Inkeri Lokki, Tiina Jääskeläinen, Eija Kortelainen, Sanni Ruotsalainen, Juha Karjalainen, Samuli Ripatti, Anna Kivioja, Triin Laisk, Johannes Kettunen, Anneli Pouta, Katja Kivinen, Eero Kajantie, Seppo Heinonen, Juha Kere, Hannele Laivuori, Eeva Ekholm, Reija Hietala-Koivu, Leea Keski‐Nisula, Kaarin Mäkikallio, Jukka Uotila, Susanna Sainio, Terhi Saisto, Marja Vääräsmäki, Tia Aalto-Viljakainen, Leena Georgiadis, Jenni Heikkinen‐Eloranta, Miira M. Klemetti, Sanna Suomalainen‐König, Satu Wedenoja, Satu Leminen, Aija Lähdesmäki, Susanna Mehtälä, Christina Salmén, Aarno Palotie, Mark J. Daly, Bridget Riley-Gills, Howard J. Jacob, Dirk S. Paul, Athena Matakidou, Adam Platt, Heiko Runz, Sally John, George Okafo, Nathan Lawless, Robert M. Plenge, Joseph Maranville, Mark I. McCarthy, Julie Hunkapiller, Margaret G. Ehm, Kirsi Auro, Simonne Longerich, Caroline S. Fox, Anders Mälarstig, K. Klinger, Deepak Raipal, Eric Green, Robert Graham, Robert Yang, Chris O ́Donnell, Tomi P. Mäkelä, Jaakko Kaprio, Petri Virolainen, Antti Hakanen, Terhi Kilpi, Markus Perola, Jukka Partanen, Anne Pitkäranta, Juhani Junttila, Raisa Serpi, Tarja Laitinen, Veli‐Matti Kosma, Jari A. Laukkanen, Marco Hautalahti, Outi Tuovila, Raimo Pakkanen, Jeffrey F. Waring, Bridget Riley‐Gillis, Fedik Rahimov, Ioanna Tachmazidou, Chia‐Yen Chen, Zhihao Ding, Marc Jung, Shameek Biswas, Rion Pendergrass, David Pulford, Neha Raghavan, Adriana Huertas‐Vázquez, Jae-Hoon Sul, Xinli Hu, Sahar V. Mozaffari, Dawn Waterworth, Nicole Renaud, Ma ́en Obeidat, Johanna Schleutker, Mikko Arvas, Olli Carpén, Reetta Hinttala, Arto Mannermaa
Abstract
Importance: A genetic contribution to preeclampsia susceptibility has been established but is still incompletely understood. Objective: To disentangle the underlying genetic architecture of preeclampsia and preeclampsia or other maternal hypertension during pregnancy with a genome-wide association study (GWAS) of hypertensive disorders of pregnancy. Design, Setting, and Participants: This GWAS included meta-analyses in maternal preeclampsia and a combination phenotype encompassing maternal preeclampsia and preeclampsia or other maternal hypertensive disorders. Two overlapping phenotype groups were selected for examination, namely, preeclampsia and preeclampsia or other maternal hypertension during pregnancy. Data from the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC, 1990-2011), Finnish FinnGen project (1964-2019), Estonian Biobank (1997-2019), and the previously published InterPregGen consortium GWAS were combined. Individuals with preeclampsia or other maternal hypertension during pregnancy and control individuals were selected from the cohorts based on relevant International Classification of Diseases codes. Data were analyzed from July 2020 to February 2023. Exposures: The association of a genome-wide set of genetic variants and clinical risk factors was analyzed for the 2 phenotypes. Results: A total of 16 743 women with prior preeclampsia and 15 200 with preeclampsia or other maternal hypertension during pregnancy were obtained from FINNPEC, FinnGen, Estonian Biobank, and the InterPregGen consortium study (respective mean [SD] ages at diagnosis: 30.3 [5.5], 28.7 [5.6], 29.7 [7.0], and 28 [not available] years). The analysis found 19 genome-wide significant associations, 13 of which were novel. Seven of the novel loci harbor genes previously associated with blood pressure traits (NPPA, NPR3, PLCE1, TNS2, FURIN, RGL3, and PREX1). In line with this, the 2 study phenotypes showed genetic correlation with blood pressure traits. In addition, novel risk loci were identified in the proximity of genes involved in the development of placenta (PGR, TRPC6, ACTN4, and PZP), remodeling of uterine spiral arteries (NPPA, NPPB, NPR3, and ACTN4), kidney function (PLCE1, TNS2, ACTN4, and TRPC6), and maintenance of proteostasis in pregnancy serum (PZP). Conclusions and Relevance: The findings indicate that genes related to blood pressure traits are associated with preeclampsia, but many of these genes have additional pleiotropic effects on cardiometabolic, endothelial, and placental function. Furthermore, several of the associated loci have no known connection with cardiovascular disease but instead harbor genes contributing to maintenance of successful pregnancy, with dysfunctions leading to preeclampsialike symptoms.