Genetic Risk Factors Associated With Preeclampsia and Hypertensive Disorders of Pregnancy
Authors: Tyrmi Jaakko S. , Kaartokallio Tea , Lokki A. Inkeri , Jääskeläinen Tiina , Kortelainen Eija , Ruotsalainen Sanni , Karjalainen Juha , Ripatti Samuli , Kivioja Anna , Laisk Triin , Kettunen Johannes , Pouta Anneli , Kivinen Katja , Kajantie Eero , Heinonen Seppo , Kere Juha , Laivuori Hannele ,   FINNPEC Study Group, FinnGen Project, and the Estonian Biobank Research Team, Ekholm Eeva , Hietala Reija , Keski-Nisula Leea , Mäkikallio Kaarin , Uotila Jukka , Sainio Susanna , Saisto Terhi , Vääräsmäki Marja , Aalto-Viljakainen Tia , Georgiadis Leena , Heikkinen-Eloranta Jenni , Klemetti Miira M. , Suomalainen-König Sanna , Wedenoja Satu , Leminen Satu , Lähdesmäki Aija , Mehtälä Susanna , Salmén Christina , Palotie Aarno , Daly Mark , Riley-Gills Bridget , Jacob Howard , Paul Dirk , Matakidou Athena , Platt Adam , Runz Heiko , John Sally , Okafo George , Lawless Nathan , Plenge Robert , Maranville Joseph , McCarthy Mark , Hunkapiller Julie , Ehm Margaret G. , Auro Kirsi , Longerich Simonne , Fox Caroline , Mälarstig Anders , Klinger Katherine , Raipal Deepak , Green Eric , Graham Robert , Yang Robert , O´Donnell Chris , Mäkelä Tomi P. , Kaprio Jaakko , Virolainen Petri , Hakanen Antti , Kilpi Terhi , Perola Markus , Partanen Jukka , Pitkäranta Anne , Junttila Juhani , Serpi Raisa , Laitinen Tarja , Kosma Veli-Matti , Laukkanen Jari , Hautalahti Marco , Tuovila Outi , Pakkanen Raimo , Waring Jeffrey , Riley-Gillis Bridget , Rahimov Fedik , Tachmazidou Ioanna , Chen Chia-Yen , Ding Zhihao , Jung Marc , Biswas Shameek , Pendergrass Rion , Pulford David , Raghavan Neha , Huertas-Vazquez Adriana , Sul Jae-Hoon , Hu Xinli , Mozaffari Sahar , Waterworth Dawn , Renaud Nicole , Obeidat Ma´en , Schleutker Johanna , Arvas Mikko , Carpén Olli , Hinttala Reetta , Mannermaa Arto , Aalto-Setälä Katriina , Kähönen Mika , Mäkelä Johanna , Kälviäinen Reetta , Julkunen Valtteri , Soininen Hilkka , Remes Anne , Hiltunen Mikko , Peltola Jukka , Raivio Minna , Tienari Pentti , Rinne Juha , Kallionpää Roosa , Partanen Juulia , Abbasi Ali , Ziemann Adam , Smaoui Nizar , Lehtonen Anne , Eaton Susan , Lahdenperä Sanni , Bowers Natalie , Teng Edmond , Xu Fanli , Addis Laura , Eicher John , Li Qingqin S , He Karen , Khramtsova Ekaterina , Färkkilä Martti , Koskela Jukka , Pikkarainen Sampsa , Jussila Airi , Kaukinen Katri , Blomster Timo , Kiviniemi Mikko , Voutilainen Markku , Lu Tim , McCarthy Linda , Hart Amy , Guan Meijian , Miller Jason , Kalpala Kirsi , Miller Melissa , Eklund Kari , Palomäki Antti , Isomäki Pia , Pirilä Laura , Kaipiainen-Seppänen Oili , Huhtakangas Johanna , Mars Nina , Lertratanakul Apinya , Close David , Hochfeld Marla , Gordillo Jorge Esparza , Farias Fabiana , Bing Nan , Pelkonen Margit , Kauppi Paula , Kankaanranta Hannu , Harju Terttu , Lahesmaa Riitta , Mackay Alex , Lassi Glenda , Chen Hubert , Betts Joanna , Mishra Rajashree , Mouded Majd , Ngo Debby , Niiranen Teemu , Vaura Felix , Salomaa Veikko , Metsärinne Kaj , Aittokallio Jenni , Hernesniemi Jussi , Gordin Daniel , Sinisalo Juha , Taskinen Marja-Riitta , Tuomi Tiinamaija , Hiltunen Timo , Elliott Amanda , Reeve Mary Pat , Challis Benjamin , Chu Audrey , Reilly Dermot , Mendelson Mike , Parkkinen Jaakko , Meretoja Tuomo , Joensuu Heikki , Mattson Johanna , Salminen Eveliina , Auranen Annika , Karihtala Peeter , Auvinen Päivi , Elenius Klaus , Pitkänen Esa , Popovic Relja , Schutzman Jennifer , Kulkarni Diptee , Porello Alessandro , Loboda Andrey , Lehtonen Heli , McDonough Stefan , Vuoti Sauli , Kaarniranta Kai , Turunen Joni A , Ollila Terhi , Uusitalo Hannu , Liu Mengzhen , Loomis Stephanie , Strauss Erich , Chen Hao , Tasanen Kaisa , Huilaja Laura , Hannula-Jouppi Katariina , Salmi Teea , Peltonen Sirkku , Koulu Leena , Choy David , Wu Ying , Pussinen Pirkko , Salminen Aino , Salo Tuula , Rice David , Nieminen Pekka , Palotie Ulla , Siponen Maria , Suominen Liisa , Mäntylä Päivi , Gursoy Ulvi , Anttonen Vuokko , Sipilä Kirsi , Kurra Venla , Kotaniemi-Talonen Laura , Heikinheimo Oskari , Kalliala Ilkka , Aaltonen Lauri , Jokimaa Varpu , Kettunen Johannes , Uimari Outi , Morin-Papunen Laure , Niinimäki Maarit , Piltonen Terhi , Widen Elisabeth , Tukiainen Taru , Välimäki Niko , Laakkonen Eija , Silven Heidi , Sliz Eeva , Arffman Riikka , Savukoski Susanna , Pujol Natalia , Kumar Janet , Hovatta Iiris , Isometsä Erkki , Veerapen Kumar , Ollila Hanna , Suvisaari Jaana , Als Thomas D. , Mäkitie Antti , Bizaki-Vallaskangas Argyro , Toppila-Salmi Sanna , Willberg Tytti , Saarentaus Elmo , Aarnisalo Antti , Rahikkala Elisa , Aittomäki Kristiina , Åberg Fredrik , Kurki Mitja , Ripatti Samuli , Karjalainen Juha , Havulinna Aki , Mehtonen Juha , Palta Priit , Hassan Shabbeer , Parolo Pietro Della Briotta , Zhou Wei , Maasha Mutaamba , Lemmelä Susanna , Rivas Manuel , Niemi Mari E. , Liu Aoxing , Lehisto Arto , Ganna Andrea , Llorens Vincent , Heyne Henrike , Rämö Joel , Rodosthenous Rodos , Strausz Satu , Palotie Tuula , Palin Kimmo , Garcia-Tabuenca Javier , Siirtola Harri , Kiiskinen Tuomo , Lee Jiwoo , Tsuo Kristin , Kristiansson Kati , Hyvärinen Kati , Ritari Jarmo , Pylkäs Katri , Karjalainen Minna , Mantere Tuomo , Kangasniemi Eeva , Heikkinen Sami , Pitkänen Nina , Lessard Samuel , Chatelain Clément , Terho Perttu , Soini Sirpa , Punkka Eero , Siltanen Sanna , Kuopio Teijo , Jalanko Anu , Shen Huei-Yi , Kajanne Risto , Aavikko Mervi , Kanai Masahiro , Laivuori Hannele , Lahtela L. Elisa , Kaunisto Mari , Kilpeläinen Elina , Sipilä Timo P. , Dada Oluwaseun Alexander , Ghazal Awaisa , Kytölä Anastasia , Weldatsadik Rigbe , Donner Kati , Loukola Anu , Laiho Päivi , Sistonen Tuuli , Kaiharju Essi , Laukkanen Markku , Järvensivu Elina , Lähteenmäki Sini , Männikkö Lotta , Wong Regis , Toivola Auli , Brunfeldt Minna , Mattsson Hannele , Koskelainen Sami , Hiekkalinna Tero , Paajanen Teemu , Pärn Kalle , Kals Mart , Luo Shuang , Sinha Vishal , Niemi Marianna , Gracia-Tabuenca Javier , Helminen Mika , Luukkaala Tiina , Vähätalo Iida , Pitkänen Jyrki , Smith Sarah , Southerington Tom , Metspalu Andres , Esko Tõnu , Nelis Mari , Milani Lili , Mägi Reedik , Hudjashov Georgi 
Published: June 2023

ImportanceA genetic contribution to preeclampsia susceptibility has been established but is still incompletely understood.ObjectiveTo 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 ParticipantsThis 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.ExposuresThe association of a genome-wide set of genetic variants and clinical risk factors was analyzed for the 2 phenotypes.ResultsA 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 RelevanceThe 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.