Genome-wide association scan identifies a risk locus for preeclampsia on 2q14, near the inhibin, beta B gene

Matthew P. Johnson, Shaun P. Brennecke, Christine E. East, Harald H H Göring, Jack W. Kent, Thomas D. Dyer, Joanne M. Said, Linda T. Roten, Ann Charlotte Iversen, Lawrence J. Abraham, Seppo Heinonen, Eero Kajantie, Juha Kere, Katja Kivinen, Anneli Pouta, Hannele Laivuori, Rigmor Austgulen, John Blangero, Eric K. Moses

Research output: Contribution to journalArticle

50 Citations (Scopus)

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).

Original languageEnglish (US)
Article numbere33666
JournalPLoS One
Volume7
Issue number3
DOIs
StatePublished - Mar 14 2012
Externally publishedYes

Fingerprint

pre-eclampsia
inhibin
Inhibins
Genome-Wide Association Study
Pre-Eclampsia
Single Nucleotide Polymorphism
Genes
loci
genes
Obstetrics
Decidua
bioinformatics
Finland
Norway
Bioinformatics
medicine
ancestry
Computational Biology
Medicine
pregnancy

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Johnson, M. P., Brennecke, S. P., East, C. E., Göring, H. H. H., Kent, J. W., Dyer, T. D., ... Moses, E. K. (2012). Genome-wide association scan identifies a risk locus for preeclampsia on 2q14, near the inhibin, beta B gene. PLoS One, 7(3), [e33666]. https://doi.org/10.1371/journal.pone.0033666

Genome-wide association scan identifies a risk locus for preeclampsia on 2q14, near the inhibin, beta B gene. / Johnson, Matthew P.; Brennecke, Shaun P.; East, Christine E.; Göring, Harald H H; Kent, Jack W.; Dyer, Thomas D.; Said, Joanne M.; Roten, Linda T.; Iversen, Ann Charlotte; Abraham, Lawrence J.; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Kivinen, Katja; Pouta, Anneli; Laivuori, Hannele; Austgulen, Rigmor; Blangero, John; Moses, Eric K.

In: PLoS One, Vol. 7, No. 3, e33666, 14.03.2012.

Research output: Contribution to journalArticle

Johnson, MP, Brennecke, SP, East, CE, Göring, HHH, Kent, JW, Dyer, TD, Said, JM, Roten, LT, Iversen, AC, Abraham, LJ, Heinonen, S, Kajantie, E, Kere, J, Kivinen, K, Pouta, A, Laivuori, H, Austgulen, R, Blangero, J & Moses, EK 2012, 'Genome-wide association scan identifies a risk locus for preeclampsia on 2q14, near the inhibin, beta B gene', PLoS One, vol. 7, no. 3, e33666. https://doi.org/10.1371/journal.pone.0033666
Johnson, Matthew P. ; Brennecke, Shaun P. ; East, Christine E. ; Göring, Harald H H ; Kent, Jack W. ; Dyer, Thomas D. ; Said, Joanne M. ; Roten, Linda T. ; Iversen, Ann Charlotte ; Abraham, Lawrence J. ; Heinonen, Seppo ; Kajantie, Eero ; Kere, Juha ; Kivinen, Katja ; Pouta, Anneli ; Laivuori, Hannele ; Austgulen, Rigmor ; Blangero, John ; Moses, Eric K. / Genome-wide association scan identifies a risk locus for preeclampsia on 2q14, near the inhibin, beta B gene. In: PLoS One. 2012 ; Vol. 7, No. 3.
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