title: OS046. Genome-wide association scans identify novel maternalsusceptibility loci for preeclampsia.
abstract: BACKGROUND
  We have successfully utilized a family-based study design to localize several positional candidate preeclampsia susceptibility genes to chromosomes 2q22(ACVR2A,LCT,LRP1B,RND3,GCA),5q (ERAP2) and 13q(TNFSF13B). We now report on our continued positional cloning efforts using an alternative genome-wide association (GWA) mapping strategy in large Caucasian case-control cohorts from Australia and Norway.
  
  
  OBJECTIVE
  To identify maternal genetic risk loci for preeclampsia.
  
  
  METHODS
  The unrelated Australian samples (545 cases,547 controls) were genotyped using Illumina BeadChip technology (700K loci) and have been analyzed using PLINK. All unrelated Norwegian samples were genotyped across several Illumina BeadChip substrates and consist of 847 cases (700K loci) and 638 controls. The Norwegian control samples originate from other HUNT studies pertaining to migraine (n=95,700K loci), lung cancer (n=89,370K loci) and normal brain pathology (n=454,2.5M loci). To analyze a concordant set of 2.5-3 million genotypes across all Norwegian samples we are currently using MaCH to impute those loci not directly genotyped. The Norwegian GWA data will be analyzed in SOLAR utilizing empirical kinship estimates to account for any distant relatedness.
  
  
  RESULTS
  1078 Australian samples (538 cases,540 controls) and 648, 175 SNPs passed our quality control metrics. Two SNP associations (rs7579169,p=3.6×10(-7); rs12711941,p=4.3×10(-7)) satisfied our genome-wide significant threshold (p<5.1×10(-7)). These SNPs reside less than 15kb downstream from the 3 terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. Sequencing of the INHBB locus in our patient cohort identified a third intergenic SNP to significantly associate with preeclampsia (rs7576192,p=1.5×10(-7)). These three SNPs confer risk (OR>1.56) and are in strong linkage disequilibrium with each other (r(2)>0.9) but not with any other genotyped SNP ±200kb. The analysis of the Norwegian GWAS is underway.
  
  
  CONCLUSIONS
  The Australian GWAS has identified a novel preeclampsia risk locus on chromosome 2q. The INHBB gene closest to our SNP associations is a plausible positional candidate susceptibility gene. There is a substantive body of evidence implicating inhibins, activins and other members of the TGF-βsuperfamily to have a role in the development of preeclampsia. The biological connection between ACVR2A and INHBB leads us to speculate that our linkage-based and GWA-based study designs, respectively, have identified a key biological pathway involved in susceptibility to preeclampsia.
authors.affiliation: Texas Biomedical Research Institute, San Antonio, United States.
authors.forename: M
authors.initials: M
authors.lastname: Johnson
authors.affiliation: University of Melbourne, Melbourne, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Brennecke
authors.affiliation: Norwegian University of Science & Technology, Trondheim, Norway.
authors.forename: A-C
authors.initials: AC
authors.lastname: Iversen
authors.affiliation: University of Melbourne, Melbourne, Australia.
authors.forename: C
authors.initials: C
authors.lastname: East
authors.affiliation: Norwegian University of Science & Technology, Trondheim, Norway.
authors.forename: G
authors.initials: G
authors.lastname: Olsen
authors.affiliation: Texas Biomedical Research Institute, San Antonio, United States.
authors.forename: J
authors.initials: J
authors.lastname: Kent
authors.affiliation: Texas Biomedical Research Institute, San Antonio, United States.
authors.forename: T
authors.initials: T
authors.lastname: Dyer
authors.affiliation: University of Melbourne, Melbourne, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Said
authors.affiliation: Norwegian University of Science & Technology, Trondheim, Norway.
authors.forename: L
authors.initials: L
authors.lastname: Roten
authors.affiliation: University of Western Australia, Perth, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Abraham
authors.affiliation: Oslo University Hospital, Oslo, Norway.
authors.forename: J-A
authors.initials: JA
authors.lastname: Zwart
authors.affiliation: Oslo University Hospital, Oslo, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Winsvold
authors.affiliation: Norwegian University of Science & Technology, Trondheim, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Håberg
authors.affiliation: Translational Genomics Research Institute, Phoenix, United States.
authors.forename: M
authors.initials: M
authors.lastname: Huentelman
authors.affiliation: Norwegian University of Science & Technology, Trondheim, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Krokan
authors.affiliation: Norwegian University of Science & Technology, Trondheim, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Gabrielsen
authors.affiliation: Norwegian University of Science & Technology, Trondheim, Norway.
authors.forename: R
authors.initials: R
authors.lastname: Austgulen
authors.affiliation: Texas Biomedical Research Institute, San Antonio, United States.
authors.forename: J
authors.initials: J
authors.lastname: Blangero
authors.affiliation: University of Western Australia, Perth, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Moses