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).

Pregnancy-Related Liver Disorders

“…49, 51 The role of various maternal genetic factors, 52 behavioural and environmental factors in pathogenesis of pre-eclampsia are under study.…”

A follow-up linkage study of Finnish pre-eclampsia families identifies a new fetal susceptibility locus on chromosome 18

“…5 Epidemiological research has demonstrated that both maternal and fetal genes are important in the pathogenesis. 6 Genome-wide linkage and association studies carried out by us 7 and others [8][9][10][11][12][13] have revealed a number of maternal susceptibility loci.…”

“…14 The results yielded by candidate gene studies have, thus far, proved inconsistent and addressed mainly the maternal genotype and the susceptibility loci therein. 4,[9][10][11][12][13] In this follow-up study, we make comparisons of the earlier and more recent methods regarding the linkage findings in pre-eclampsia. In particular, we wish to shed light on the assumed genetic connection between the maternal and fetal pre-eclamptic phenotypes.…”

Searching for genes involved in hypertension development in special populations: children and pre-eclamptic women. Where are we standing now?

“…In the attempt to find out genetic loci associated to hypertensive disorders in pregnancy, mainly PE, different genome-wide scan have been performed in the past [201][202][203][204][205]. These genome-wide searches have recognized 'hot spot regions' in particular on chromosomes 2p, 6p, 9q, 11p and 19q, but in those loci many genes are present and no robust association have been presented so far.…”