Article

Genome-Wide Association Scan Identifies a Risk Locus for Preeclampsia on 2q14, Near the Inhibin, Beta B Gene

Matthew P. JohnsonDepartment of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of AmericaShaun P. BrenneckeDepartment of Perinatal Medicine/Department of Obstetrics and Gynaecology, Royal Women's Hospital and University of Melbourne, Parkville, Victoria, AustraliaChristine EastDepartment of Perinatal Medicine/Department of Obstetrics and Gynaecology, Royal Women's Hospital and University of Melbourne, Parkville, Victoria, AustraliaHarald H.H. GöringDepartment of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of AmericaJack W. KentDepartment of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of AmericaThomas D. DyerDepartment of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of AmericaJoanne SaidDepartment of Perinatal Medicine/Department of Obstetrics and Gynaecology, Royal Women's Hospital and University of Melbourne, Parkville, Victoria, AustraliaLinda T. RotenDepartment of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, NorwayAnn‐Charlotte IversenDepartment of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, NorwayLawrence J. AbrahamThe School of Biomedical Biomolecular and Chemical Sciences, The University of Western Australia, Perth, Western Australia, AustraliaSeppo HeinonenDepartment of Obstetrics and Gynecology, Kuopio University Hospital, and University of Eastern Finland, Kuopio, FinlandEero KajantieChildren's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, FinlandJuha KereDepartment of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, Stockholm, SwedenKatja KivinenWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United KingdomAnneli PoutaDepartment of Children, Young People and Families, National Institute for Health and Welfare, Oulu, FinlandHannele LaivuoriHaartman Institute, Department of Medical Genetics, University of Helsinki, Helsinki, Finlandfor the FINNPEC Study GroupDepartment of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, NorwayRigmor AustgulenDepartment of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, NorwayJohn BlangeroDepartment of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of AmericaEric K. MosesDepartment of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America

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Abstract

Elucidating the genetic architecture of preeclampsia is a major goal in obstetric medicine. We have performed a genome-wide association study (GWAS) for preeclampsia in unrelated Australian individuals of Caucasian ancestry using the Illumina OmniExpress-12 BeadChip to successfully genotype 648,175 SNPs in 538 preeclampsia cases and 540 normal pregnancy controls. Two SNP associations (rs7579169, p = 3.58×10(-7), OR = 1.57; rs12711941, p = 4.26×10(-7), OR = 1.56) satisfied our genome-wide significance threshold (modified Bonferroni p<5.11×10(-7)). These SNPs reside in an intergenic region less than 15 kb downstream from the 3' terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. They are in linkage disequilibrium (LD) with each other (r(2) = 0.92), but not (r(2)<0.80) with any other genotyped SNP ±250 kb. DNA re-sequencing in and around the INHBB structural gene identified an additional 25 variants. Of the 21 variants that we successfully genotyped back in the case-control cohort the most significant association observed was for a third intergenic SNP (rs7576192, p = 1.48×10(-7), OR = 1.59) in strong LD with the two significant GWAS SNPs (r(2)>0.92). We attempted to provide evidence of a putative regulatory role for these SNPs using bioinformatic analyses and found that they all reside within regions of low sequence conservation and/or low complexity, suggesting functional importance is low. We also explored the mRNA expression in decidua of genes ±500 kb of INHBB and found a nominally significant correlation between a transcript encoded by the EPB41L5 gene, ∼250 kb centromeric to INHBB, and preeclampsia (p = 0.03). We were unable to replicate the associations shown by the significant GWAS SNPs in case-control cohorts from Norway and Finland, leading us to conclude that it is more likely that these SNPs are in LD with as yet unidentified causal variant(s).

Identifiers

DOI: 10.1371/journal.pone.0033666

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