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

Ralph McGinnis, Valgerdur Steinthorsdottir, Nicholas O Williams, Gudmar Thorleifsson, Scott Shooter, Sigrun Hjartardottir, Suzannah Bumpstead, Lilja Stefansdottir, Lucy Hildyard, Jon K Sigurdsson, John P Kemp, Gabriela B Silva, Liv Cecilie V Thomsen, Tiina Jääskeläinen, Eero Kajantie, Sally Chappell, Noor Kalsheker, Ashley Moffett, Susan Hiby, Wai Kwong Lee & 25 others Sandosh Padmanabhan, Nigel A B Simpson, Vivien A Dolby, Eleonora Staines-Urias, Stephanie M Engel, Anita Haugan, Lill Trogstad, Gulnara Svyatova, Nodira Zakhidova, Dilbar Najmutdinova, Anna F Dominiczak, Håkon K Gjessing, Juan P Casas, Frank Dudbridge, James J Walker, Fiona Broughton Pipkin, Unnur Thorsteinsdottir, Reynir T Geirsson, Debbie A Lawlor, Ann-Charlotte Iversen, Per Magnus, Hannele Laivuori, Kari Stefansson, Linda Morgan, FINNPEC Consortium

Research output: Contribution to journalLetter

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1255-1260
Number of pages6
JournalNature Genetics
Volume49
Early online date19 Jun 2017
DOIs
Publication statusPublished - 2017

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Pre-Eclampsia
Genome
Pregnancy
Genome-Wide Association Study
Pregnancy Proteins
Vascular Endothelial Growth Factor Receptor-1
Maternal Death
Birth Weight
Cause of Death
Protein Isoforms
Mothers
Pathology
Genes

Keywords

  • Journal Article

Cite this

McGinnis, R., Steinthorsdottir, V., Williams, N. O., Thorleifsson, G., Shooter, S., Hjartardottir, S., ... FINNPEC Consortium (2017). Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. Nature Genetics, 49, 1255-1260. https://doi.org/10.1038/ng.3895

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. / McGinnis, Ralph; Steinthorsdottir, Valgerdur; Williams, Nicholas O; Thorleifsson, Gudmar; Shooter, Scott; Hjartardottir, Sigrun; Bumpstead, Suzannah; Stefansdottir, Lilja; Hildyard, Lucy; Sigurdsson, Jon K; Kemp, John P; Silva, Gabriela B; Thomsen, Liv Cecilie V; Jääskeläinen, Tiina; Kajantie, Eero; Chappell, Sally; Kalsheker, Noor; Moffett, Ashley; Hiby, Susan; Lee, Wai Kwong; Padmanabhan, Sandosh; Simpson, Nigel A B; Dolby, Vivien A; Staines-Urias, Eleonora; Engel, Stephanie M; Haugan, Anita; Trogstad, Lill; Svyatova, Gulnara; Zakhidova, Nodira; Najmutdinova, Dilbar; Dominiczak, Anna F; Gjessing, Håkon K; Casas, Juan P; Dudbridge, Frank; Walker, James J; Pipkin, Fiona Broughton; Thorsteinsdottir, Unnur; Geirsson, Reynir T; Lawlor, Debbie A; Iversen, Ann-Charlotte; Magnus, Per; Laivuori, Hannele; Stefansson, Kari; Morgan, Linda; FINNPEC Consortium.

In: Nature Genetics, Vol. 49, 2017, p. 1255-1260.

Research output: Contribution to journalLetter

McGinnis, R, Steinthorsdottir, V, Williams, NO, Thorleifsson, G, Shooter, S, Hjartardottir, S, Bumpstead, S, Stefansdottir, L, Hildyard, L, Sigurdsson, JK, Kemp, JP, Silva, GB, Thomsen, LCV, Jääskeläinen, T, Kajantie, E, Chappell, S, Kalsheker, N, Moffett, A, Hiby, S, Lee, WK, Padmanabhan, S, Simpson, NAB, Dolby, VA, Staines-Urias, E, Engel, SM, Haugan, A, Trogstad, L, Svyatova, G, Zakhidova, N, Najmutdinova, D, Dominiczak, AF, Gjessing, HK, Casas, JP, Dudbridge, F, Walker, JJ, Pipkin, FB, Thorsteinsdottir, U, Geirsson, RT, Lawlor, DA, Iversen, A-C, Magnus, P, Laivuori, H, Stefansson, K, Morgan, L & FINNPEC Consortium 2017, 'Variants in the fetal genome near FLT1 are associated with risk of preeclampsia', Nature Genetics, vol. 49, pp. 1255-1260. https://doi.org/10.1038/ng.3895
McGinnis R, Steinthorsdottir V, Williams NO, Thorleifsson G, Shooter S, Hjartardottir S et al. Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. Nature Genetics. 2017;49:1255-1260. https://doi.org/10.1038/ng.3895
McGinnis, Ralph ; Steinthorsdottir, Valgerdur ; Williams, Nicholas O ; Thorleifsson, Gudmar ; Shooter, Scott ; Hjartardottir, Sigrun ; Bumpstead, Suzannah ; Stefansdottir, Lilja ; Hildyard, Lucy ; Sigurdsson, Jon K ; Kemp, John P ; Silva, Gabriela B ; Thomsen, Liv Cecilie V ; Jääskeläinen, Tiina ; Kajantie, Eero ; Chappell, Sally ; Kalsheker, Noor ; Moffett, Ashley ; Hiby, Susan ; Lee, Wai Kwong ; Padmanabhan, Sandosh ; Simpson, Nigel A B ; Dolby, Vivien A ; Staines-Urias, Eleonora ; Engel, Stephanie M ; Haugan, Anita ; Trogstad, Lill ; Svyatova, Gulnara ; Zakhidova, Nodira ; Najmutdinova, Dilbar ; Dominiczak, Anna F ; Gjessing, Håkon K ; Casas, Juan P ; Dudbridge, Frank ; Walker, James J ; Pipkin, Fiona Broughton ; Thorsteinsdottir, Unnur ; Geirsson, Reynir T ; Lawlor, Debbie A ; Iversen, Ann-Charlotte ; Magnus, Per ; Laivuori, Hannele ; Stefansson, Kari ; Morgan, Linda ; FINNPEC Consortium. / Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. In: Nature Genetics. 2017 ; Vol. 49. pp. 1255-1260.
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AU - McGinnis, Ralph

AU - Steinthorsdottir, Valgerdur

AU - Williams, Nicholas O

AU - Thorleifsson, Gudmar

AU - Shooter, Scott

AU - Hjartardottir, Sigrun

AU - Bumpstead, Suzannah

AU - Stefansdottir, Lilja

AU - Hildyard, Lucy

AU - Sigurdsson, Jon K

AU - Kemp, John P

AU - Silva, Gabriela B

AU - Thomsen, Liv Cecilie V

AU - Jääskeläinen, Tiina

AU - Kajantie, Eero

AU - Chappell, Sally

AU - Kalsheker, Noor

AU - Moffett, Ashley

AU - Hiby, Susan

AU - Lee, Wai Kwong

AU - Padmanabhan, Sandosh

AU - Simpson, Nigel A B

AU - Dolby, Vivien A

AU - Staines-Urias, Eleonora

AU - Engel, Stephanie M

AU - Haugan, Anita

AU - Trogstad, Lill

AU - Svyatova, Gulnara

AU - Zakhidova, Nodira

AU - Najmutdinova, Dilbar

AU - Dominiczak, Anna F

AU - Gjessing, Håkon K

AU - Casas, Juan P

AU - Dudbridge, Frank

AU - Walker, James J

AU - Pipkin, Fiona Broughton

AU - Thorsteinsdottir, Unnur

AU - Geirsson, Reynir T

AU - Lawlor, Debbie A

AU - Iversen, Ann-Charlotte

AU - Magnus, Per

AU - Laivuori, Hannele

AU - Stefansson, Kari

AU - Morgan, Linda

AU - FINNPEC Consortium

PY - 2017

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N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1038/ng.3895

DO - 10.1038/ng.3895

M3 - Letter

VL - 49

SP - 1255

EP - 1260

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -