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

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.

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Figure 1: Manhattan plots showing GWAS results for 2,658 cases and 308,292 controls across all autosomes and a detailed view near FLT1 on chromosome 13.
Figure 2: Key observations about rs4769613 in relation to preeclampsia.

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Acknowledgements

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/).

We are grateful to all the families from Iceland, Norway, Finland and the UK who took part in this study and for the work of teams of volunteers, managers, midwives, nurses, doctors, computer and laboratory technicians, clerical workers, research scientists and receptionists who made this study possible.

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Manuscript preparation: R.M., V.S., N.O.W., L.C.V.T., A.-C.I., L.M. All authors contributed to critical analysis and revision of the manuscript. Study design: R.M., V.S., N.O.W., T.J., S.C., N.K., N.A.B.S., V.A.D., E.S.-U., S.M.E., A.H., L.T., G.S., N.Z., D.N., A.F.D., H.K.G., J.P.C., F.D., J.J.W., F.B.P., U.T., D.A.L., A.-C.I., P.M., H.L., K.S., L.M., A.M. Phenotyping: S.H., G.B.S., L.C.V.T., T.J., E.K., FINNPEC Consortium, GOPEC Consortium, J.J.W., F.B.P., R.T.G., D.A.L., H.L., L.M. Genotyping and quality control: S.S., S.B., L.H., W.K.L., S.P., U.T., H.L., A.M. GWAS data analysis: R.M., V.S., N.O.W., G.T., S.S., L.S., J.K.S., J.P.K. Immunohistochemistry: G.B.S., L.C.V.T., A.-C.I. Biomarker measurement: H.L. Interpretation: R.M., V.S., N.O.W., G.T., J.P.K., L.C.V.T., T.J., E.K., S.C., N.K., N.A.B.S., V.D., E.S.-U., L.T., H.K.G., F.D., J.J.W., F.B.P., D.A.L., A.-C.I., P.M., H.L., K.S., L.M.

Corresponding authors

Correspondence to Ralph McGinnis or Valgerdur Steinthorsdottir or Linda Morgan.

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Competing interests

V.S., G.T., L.S., J.K.S., U.T. and K.S. are employees of the biotechnology firm deCODE Genetics, a subsidiary of Amgen. D.A.L. has received industry funding for biomarker research unrelated to this paper from Medtronic, Roche Diagnostics and Ferring Pharmaceuticals.

Integrated supplementary information

Supplementary Figure 1 Forest plots for GWAS and replication cohorts at independent variants near FLT1 giving evidence for association with preeclampsia.

Forest plots are presented in order of strength of association with preeclampsia (PE) (Table 1). The top line of each plot gives the variant rs number, the position on chromosome 13 (human genome build 19), the risk allele (i.e., the allele with the higher frequency in cases versus controls in the GWAS meta-analysis) with its population frequency in parentheses, the other allele and Phet, the P value for the heterogeneity of odds ratios across the five cohorts. Subsequent lines provide a breakdown of the results for each GWAS and replication cohort, including the number of cases and controls, the allelic case–control OR and its 95% confidence interval (95% CI), and the case–control association P value. [META] indicates corresponding meta-analysis results for the GWAS cohorts, the replication cohorts, or the GWAS and replication cohorts combined; each meta-analysis allelic OR is represented by a ‘diamond’ whose width corresponds to the 95% CI. The first three Forest plots give unconditional logistic regression results, and the last three plots give logistic regression results that condition out the effect of rs4769613. SNP rs11619261 is included here because it was used as a proxy for rs149427560 in the FINNPEC cohort (Table 1).

Supplementary Figure 2 Linkage disequilibrium matrix showing pairwise LD r2 values among all variants near FLT1 selected for follow-up in replication cohorts.

LD r2 values were generated by LDlink software (http://analysistools.nci.nih.gov/LDlink) from 1000 Genomes Phase 3 genotypes for all European populations. Variants are ordered by chromosomal position and shown in relation to FLT1 and POMP. Intensity of red shading (see color legend) corresponds to approximate r2 value for each variant pair and implies that the 21 follow-up variants define nine LD ‘blocks’, with high pairwise r2 within each block but low pairwise r2 for members of different blocks.

Supplementary Figure 3 rs12050029 and preeclampsia subtype meta-analysis overview.

Forest plots for preeclampsia (PE) subtypes defined by early or late onset (EO-PE, LO-PE) and by birth weight that is small for gestational age (SGA-PE) or not (non-SGA-PE). Case–control comparison shows that the G risk allele is significantly associated with LO preeclampsia (P = 1.4 × 10−5), non-SGA preeclampsia (P = 4.5 × 10−4) and SGA preeclampsia (P = 6.6 × 10−3). The strength of association does not differ between SGA and non-SGA preeclampsia.

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Supplementary Figures 1–3 and Supplementary Tables 1–9 (PDF 1115 kb)

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McGinnis, R., Steinthorsdottir, V., Williams, N. et al. Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. Nat Genet 49, 1255–1260 (2017). https://doi.org/10.1038/ng.3895

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