Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.
Ralph McGinnisValgerdur SteinthorsdottirNicholas O WilliamsGudmar ThorleifssonScott ShooterSigrun HjartardottirSuzannah BumpsteadLilja StefansdottirLucy HildyardJon K SigurdssonJohn P KempGabriela B SilvaLiv Cecilie V ThomsenTiina JääskeläinenEero KajantieSally ChappellNoor KalshekerAshley MoffettSusan HibyWai Kwong LeeSandosh PadmanabhanNigel A B SimpsonVivien A DolbyEleonora Staines-UriasStephanie M EngelAnita HauganLill TrogstadGulnara SvyatovaNodira ZakhidovaDilbar Najmutdinovanull nullnull nullAnna F DominiczakHåkon K GjessingJuan P CasasFrank DudbridgeJames J WalkerFiona Broughton PipkinUnnur ThorsteinsdottirReynir T GeirssonDebbie A LawlorAnn-Charlotte IversenPer MagnusFinnpec Hannele LaivuoriKari StefanssonLinda MorganPublished in: Nature genetics (2017)
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.
Keyphrases
- pregnancy outcomes
- tyrosine kinase
- early onset
- genome wide
- pregnant women
- copy number
- gestational age
- epidermal growth factor receptor
- dna methylation
- high fat diet
- birth weight
- acute myeloid leukemia
- preterm birth
- genome wide association study
- genome wide association
- metabolic syndrome
- machine learning
- gene expression
- high throughput
- adipose tissue
- protein protein
- amino acid