Whole-exome sequencing in multiplex preeclampsia families identifies novel candidate susceptibility genes

Melton, Phillip E.; Johnson, Matthew P.; Gokhale-Agashe, Dnyanada; Rea, Alexander J.; Ariff, Amir; Cadby, Gemma; Peralta, Juan M.; McNab, Tegan J; Allcock, Richard J. N.; Abraham, Lawrence J.; Blangero, John; Brennecke, Shaun; Moses, Eric K.

doi:10.1097/hjh.0000000000002023

Cited by 24 publications

(13 citation statements)

References 59 publications

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“…We recently showed that the fetal genome contains a preeclampsia susceptibility locus at FLT1 6 . However, previous attempts to identify maternal sequence variants associated with preeclampsia through genome-wide association scans (GWAS) or targeted gene-centric analysis have been hampered by small sample size [7][8][9][10][11] .…”

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confidence: 99%

Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Steinthórsdóttir¹,

McGinnis²,

Williams³

et al. 2020

Nat Commun

135

154

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Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.

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confidence: 99%

Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Steinthórsdóttir¹,

McGinnis²,

Williams³

et al. 2020

Nat Commun

135

154

View full text Add to dashboard Cite

show abstract

“…There have been several sequencing efforts, including whole genome, whole exome and targeted sequencing, on an array of preeclampsia phenotypes from diverse populations ( Johnson et al, 2012 ; Emmery et al, 2016 ; Kaartokallio et al, 2016 ; Thomsen et al, 2017 ; Gammill et al, 2018 ; Hansen et al, 2018 ; Soellner et al, 2018 ; Glotov et al, 2019 ; Melton et al, 2019 ; Steinthorsdottir et al, 2020 ; Zhang et al, 2020 ). There is no consensus among the published results in regards to associated genes and variants.…”

Section: Discussionmentioning

confidence: 99%

Protein Network Analysis of Whole Exome Sequencing of Severe Preeclampsia

et al. 2022

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Preeclampsia is a hypertensive disorder of pregnancy, which complicates up to 15% of US deliveries. It is an idiopathic disorder associated with several different phenotypes. We sought to determine if the genetic architecture of preeclampsia can be described by clusters of patients with variants in genes in shared protein interaction networks. We performed a case-control study using whole exome sequencing on early onset preeclamptic mothers with severe clinical features and control mothers with uncomplicated pregnancies between 2016 and 2020. A total of 143 patients were enrolled, 61 women with early onset preeclampsia with severe features based on ACOG criteria, and 82 control women at term, matched for race and ethnicity. A network analysis and visualization tool, Proteinarium, was used to confirm there are clusters of patients with shared gene networks associated with severe preeclampsia. The majority of the sequenced patients appear in two significant clusters. We identified one case dominant and one control dominant cluster. Thirteen genes were unique to the case dominated cluster. Among these genes, LAMB2, PTK2, RAC1, QSOX1, FN1, and VCAM1 have known associations with the pathogenic mechanisms of preeclampsia. Using bioinformatic analysis, we were able to identify subsets of patients with shared protein interaction networks, thus confirming our hypothesis about the genetic architecture of preeclampsia.

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“…There have been several sequencing efforts including whole genome, whole exome and targeted sequencing on an array of preeclampsia phenotypes from diverse populations 37,[55][56][57][58][59][60][61][62][63][64] . There is no consensus among the published results in regards to associated genes and variants.…”

Section: Discussionmentioning

confidence: 99%

Integrated Protein Network Analysis of Whole Exome Sequencing of Severe Preeclampsia

Schuster

Tollefson

Zarate

et al. 2020

Preprint

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To identify clusters of patients with shared networks of genes associated with early onset severe preeclampsia from whole exome sequencing data through novel bioinformatic analysis.We performed a case-control study using whole exome sequencing (WES) on early onset preeclamptic mothers with severe features delivering < 34 weeks and mothers who delivered ≥ 37 weeks. Genotype testing identified variants that were differentially abundant between cases and controls. A Protein-Protein interaction (PPI) analysis and visualization tool, Proteinarium, was implemented to identify clusters of patients with shared networks associated with severe preeclampsia.A total of 61 early onset preeclamptic women with severe features and 82 race and ethnicity matched control women at term were sequenced. We identified 8,867 predicted deleterious variants. 21 of these variants were nominally associated with preeclampsia by genotype testing. Using Proteinarium129 out of the 143 sequenced patients were assigned to statistically significant clusters, Cluster A and B (p< 0.0001). Case dominated Cluster A contained 47 of the 61 case subjects. There were 13 unique genes in the PPI network of Cluster A compared to control dominated Cluster B. Amongst these unique genes, LAMB2, PTK2, RAC1, QSOX1, FN1, and VCAM1 have known associations with the pathogenic mechanisms of preeclampsia.Our network analysis identified genes that were unique to a large cluster of patients with shared networks that provide insights for severe preeclampsia. We also identified genes imputed from the interactome that may otherwise have not been identified by conventional analysis. Strict phenotyping of both cases and controls improved the likelihood of identifying these otherwise difficult to find genetic associations. These uniquely identified genes and their associated variants are potential candidates for developing polygenic risk scores for severe preeclampsia. These results support our hypothesis on the genetic architecture of complex diseases and are generalizable to other phenotypes.

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Whole-exome sequencing in multiplex preeclampsia families identifies novel candidate susceptibility genes

Cited by 24 publications

References 59 publications

Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Protein Network Analysis of Whole Exome Sequencing of Severe Preeclampsia

Integrated Protein Network Analysis of Whole Exome Sequencing of Severe Preeclampsia

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