title: Genome-wide association scan identifies a risk locus for preeclampsia on 2q14, near the inhibin, beta B gene.
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).
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Johnson
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Brennecke
authors.forename: Christine E
authors.initials: CE
authors.lastname: East
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.forename: Jack W
authors.initials: JW
authors.lastname: Kent
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Said
authors.forename: Linda T
authors.initials: LT
authors.lastname: Roten
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Iversen
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Abraham
authors.forename: Seppo
authors.initials: S
authors.lastname: Heinonen
authors.forename: Eero
authors.initials: E
authors.lastname: Kajantie
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Katja
authors.initials: K
authors.lastname: Kivinen
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: Hannele
authors.initials: H
authors.lastname: Laivuori
authors.forename: Rigmor
authors.initials: R
authors.lastname: Austgulen
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: Eric K
authors.initials: EK
authors.lastname: Moses
mesh_terms: D001315:Australia; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D015331:Cohort Studies; D019295:Computational Biology; D005260:Female; D005387:Finland; D005786:Gene Expression Regulation; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics* / Q000378:metabolism; D009664:Norway; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy; D015203:Reproducibility of Results; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: C422402:INHBB protein, human; D028322:Inhibin-beta Subunits