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

McGinnis, R. et al. (2017) Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. Nature Genetics, 49(8), pp. 1255-1260. (doi:10.1038/ng.3895) (PMID:28628106)

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Abstract

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death1. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility2. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets3, 4. 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 preeclampsia5. 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.

Item Type:Articles (Letter)
Additional Information:Research leading to these results was conducted as part of the InterPregGen study, which received funding from the European Union Seventh Framework Programme under grant agreement no. 282540, and was supported by Wellcome Trust grant 098051. The UK Medical Research Council, the Wellcome Trust (102215/2/13/2) and the University of Bristol provide core support for ALSPAC, with additional funds for this study from the UK Medical Research Council (MC_UU_1201/5) and the European Research Council (669545) (D.A.L. and J.P.K.). The GOPEC collection was funded by British Heart Foundation Programme Grant RG/99006. The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558) and NIH/NINDS (grant no. 1 UO1 NS 047537-01 and grant no. 2 UO1 NS 047537-06A1) (P.M.). MoBa GWAS were supported in part by NICHD grant R01HD058008 (P.M. and S.M.E.). The FINNPEC study was supported by the Jane and Aatos Erkko Foundation, the Päivikki and Sakari Sohlberg Foundation, the Academy of Finland, research funds of the University of Helsinki, a government special state subsidy for health sciences (Erityisvaltionosuus funding) in the Hospital District of Helsinki and Uusimaa, the Novo Nordisk Foundation, the Finnish Foundation for Pediatric Research, the Emil Aaltonen Foundation and the Sigrid Jusélius Foundation. The Preeclampsia Study was supported by the Research Council of Norway (205400/V50 and 223255/F50) and the Liaison Committee between the Norwegian University of Science and Technology and the Central Norway Regional Health Authority (A.-C.I.). This research makes use of data generated by the Wellcome Trust Case Control Consortium (WTCCC). A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/. Funding for WTCCC, WTCCC2 and WTCCC3 was provided by the Wellcome Trust under awards 076113, 083948/Z/07/Z and 088841/Z/09/Z. This research also makes use of GWAS data from the ALSPAC study generated by G. Hemani and G. McMahon. The ALSPAC study website contains details on all the data that are available through a fully searchable data dictionary (http://www.bris.ac.uk/alspac/researchers/data-access/data-dictionary/).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lee, Dr Wai Kwong and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna
Authors: McGinnis, R., Steinthorsdottir, V., Williams, N. O., Thorleifsson, G., Shooter, S., Hjartardottir, S., Bumpstead, S., Stefansdottir, L., Hildyard, L., Sigurdsson, J. K., Kemp, J. P., Silva, G. B., Thomsen, L. C. V., Jääskeläinen, T., Kajantie, E., Chappell, S., Kalsheke, N., Moffett, A., Hiby, S., Lee, W. K., Padmanabhan, S., Simpson, N. A.B., Dolby, V. A., Staines-Urias, E., Engel, S. M., Haugan, A., Trogstad, L., Svyatova, G., Zakhidova, N., Najmutdinova, D., Dominiczak, A. F., Gjessing, H. K., Casas, J. P., Dudbridge, F., Walker, J. J., Broughton Pipkin, F., Thorsteinsdottir, U., Geirsson, R. T., Lawlor, D. A., Iversen, A.-C., Magnus, P., Laivuori, H., Stefansson, K., and Morgan, L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Nature Genetics
Publisher:Nature Publishing Group
ISSN:1061-4036
ISSN (Online):1546-1718
Published Online:19 June 2017
Copyright Holders:Copyright © 2017 Nature Publications
First Published:First published in Nature Genetics 49(8):1255-1260
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
264901Collaborative study to identify susceptibility genes in pre-eclampsiaAnna DominiczakBritish Heart Foundation (BHF)RG/99006RI CARDIOVASCULAR & MEDICAL SCIENCES
264902Collaborative study to identify susceptibility genes in pre-eclampsiaAnna DominiczakBritish Heart Foundation (BHF)RG/99006RI CARDIOVASCULAR & MEDICAL SCIENCES