Meta-Analysis

. 2017 Aug;49(8):1255-1260.

doi: 10.1038/ng.3895. Epub 2017 Jun 19.

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia

Ralph McGinnis¹, Valgerdur Steinthorsdottir², Nicholas O Williams¹, Gudmar Thorleifsson², Scott Shooter¹, Sigrun Hjartardottir³, Suzannah Bumpstead¹, Lilja Stefansdottir², Lucy Hildyard¹, Jon K Sigurdsson², John P Kemp^{4

5}, Gabriela B Silva^{6

7}, Liv Cecilie V Thomsen^{6

8}, Tiina Jääskeläinen⁹, Eero Kajantie^{10

11

12}, Sally Chappell¹³, Noor Kalsheker¹³, Ashley Moffett¹⁴, Susan Hiby¹⁴, Wai Kwong Lee¹⁵, Sandosh Padmanabhan¹⁵, Nigel A B Simpson¹⁶, Vivien A Dolby¹⁶, Eleonora Staines-Urias^{17

18}, Stephanie M Engel¹⁹, Anita Haugan²⁰, Lill Trogstad²⁰, Gulnara Svyatova²¹, Nodira Zakhidova²², Dilbar Najmutdinova²³; FINNPEC Consortium; GOPEC Consortium; Anna F Dominiczak¹⁵, Håkon K Gjessing^{20

24}, Juan P Casas²⁵, Frank Dudbridge¹⁷, James J Walker¹⁶, Fiona Broughton Pipkin²⁶, Unnur Thorsteinsdottir^{2

27}, Reynir T Geirsson³, Debbie A Lawlor^{4

28}, Ann-Charlotte Iversen⁶, Per Magnus²⁰, Hannele Laivuori^{9

29

30}, Kari Stefansson^{2

27}, Linda Morgan¹³

Collaborators, Affiliations

Affiliations

¹ Wellcome Trust Sanger Institute, Cambridge, UK.
² deCODE Genetics/Amgen, Reykjavik, Iceland.
³ Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik, Iceland.
⁴ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
⁵ University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
⁶ Centre of Molecular Inflammation Research (CEMIR) and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
⁷ St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁸ Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
⁹ Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹⁰ National Institute for Health and Welfare, Helsinki, Finland.
¹¹ Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹² PEDEGO Research Unit, Oulu University Hospital and University of Oulu, Oulu, Finland.
¹³ School of Life Sciences, University of Nottingham, Nottingham, UK.
¹⁴ Department of Pathology, University of Cambridge, Cambridge, UK.
¹⁵ BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
¹⁶ Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK.
¹⁷ Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
¹⁸ Nuffield Department of Obstetrics &Gynaecology, University of Oxford, Oxford, UK.
¹⁹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
²⁰ Norwegian Institute of Public Health, Oslo, Norway.
²¹ Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan.
²² Institute of Immunology, Uzbek Academy of Sciences, Tashkent, Uzbekistan.
²³ Republic Specialized Scientific Practical Medical Centre of Obstetrics and Gynecology, Tashkent, Uzbekistan.
²⁴ Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
²⁵ Farr Institute of Health Informatics, University College London, London, UK.
²⁶ Medical School, University of Nottingham, Nottingham, UK.
²⁷ Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
²⁸ School of Social and Community Medicine, University of Bristol, Bristol, UK.
²⁹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
³⁰ Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

PMID: 28628106
DOI: 10.1038/ng.3895

Free article

Meta-Analysis

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia

Ralph McGinnis et al. Nat Genet. 2017 Aug.

Free article

. 2017 Aug;49(8):1255-1260.

doi: 10.1038/ng.3895. Epub 2017 Jun 19.

Authors

Affiliations

¹ Wellcome Trust Sanger Institute, Cambridge, UK.
² deCODE Genetics/Amgen, Reykjavik, Iceland.
³ Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik, Iceland.
⁴ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
⁵ University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
⁶ Centre of Molecular Inflammation Research (CEMIR) and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
⁷ St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁸ Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
⁹ Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹⁰ National Institute for Health and Welfare, Helsinki, Finland.
¹¹ Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹² PEDEGO Research Unit, Oulu University Hospital and University of Oulu, Oulu, Finland.
¹³ School of Life Sciences, University of Nottingham, Nottingham, UK.
¹⁴ Department of Pathology, University of Cambridge, Cambridge, UK.
¹⁵ BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
¹⁶ Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK.
¹⁷ Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
¹⁸ Nuffield Department of Obstetrics &Gynaecology, University of Oxford, Oxford, UK.
¹⁹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
²⁰ Norwegian Institute of Public Health, Oslo, Norway.
²¹ Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan.
²² Institute of Immunology, Uzbek Academy of Sciences, Tashkent, Uzbekistan.
²³ Republic Specialized Scientific Practical Medical Centre of Obstetrics and Gynecology, Tashkent, Uzbekistan.
²⁴ Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
²⁵ Farr Institute of Health Informatics, University College London, London, UK.
²⁶ Medical School, University of Nottingham, Nottingham, UK.
²⁷ Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
²⁸ School of Social and Community Medicine, University of Bristol, Bristol, UK.
²⁹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
³⁰ Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

PMID: 28628106
DOI: 10.1038/ng.3895

Abstract

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

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Variants in the fetal genome near FLT1 are associated with risk of preeclampsia

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Variants in the fetal genome near FLT1 are associated with risk of preeclampsia

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