Analysis of the Epigenome in Multiplex Pre-eclampsia Families Identifies SORD, DGKI, and ICA1 as Novel Candidate Risk Genes

Amir Ariff, Phillip E. Melton, Shaun P. Brennecke, Eric K. Moses

Research output: Contribution to journalArticle

Abstract

Pre-eclampsia is a serious heritable disorder that affects 5-8% of pregnancies worldwide. While classical genetic studies have identified several susceptibility genes they do not fully explain the heritability of pre-eclampsia. An additional contribution to risk can be quantified by examining the epigenome, in particular the methylome, which is a representation of interactions between environmental and genetic influences on the phenotype. Current array-based epigenetic studies only examine 2-5% of the methylome. Here, we used whole-genome bisulfite sequencing (WGBS) to determine the entire methylome of 13 individuals from two multiplex pre-eclampsia families, comprising one woman with eclampsia, six women with pre-eclampsia, four women with uncomplicated normotensive pregnancies and two male relatives. The analysis of WGBS profiles using two bioinformatics platforms, BSmooth and Bismark, revealed 18,909 differentially methylated CpGs and 4157 differentially methylated regions (DMRs) concordant in females. The methylation patterns support the involvement of previously reported candidate genes, including COL4A1, SLC2A4, PER3, FLT1, GPI, LCT, DDAH1, TGFB3, DLX5, and LRP1B. Statistical analysis of DMRs revealed three novel genes significantly correlated with pre-eclampsia: sorbitol dehydrogenase (SORD, p = 9.98 x 10(-6)), diacylglycerol kinase iota (DGKI, p = 2.52 x 10(-5)), and islet cell autoantigen 1 (ICA1, 7.54 x 10(-3)), demonstrating the potential of WGBS in families for elucidating the role of epigenome in pre-eclampsia and other complex diseases.

Original languageEnglish
Article number227
Number of pages11
JournalFrontiers in Genetics
Volume10
DOIs
Publication statusPublished - 19 Mar 2019

Cite this

@article{a27849f281ba429aac48080814fe21e9,
title = "Analysis of the Epigenome in Multiplex Pre-eclampsia Families Identifies SORD, DGKI, and ICA1 as Novel Candidate Risk Genes",
abstract = "Pre-eclampsia is a serious heritable disorder that affects 5-8{\%} of pregnancies worldwide. While classical genetic studies have identified several susceptibility genes they do not fully explain the heritability of pre-eclampsia. An additional contribution to risk can be quantified by examining the epigenome, in particular the methylome, which is a representation of interactions between environmental and genetic influences on the phenotype. Current array-based epigenetic studies only examine 2-5{\%} of the methylome. Here, we used whole-genome bisulfite sequencing (WGBS) to determine the entire methylome of 13 individuals from two multiplex pre-eclampsia families, comprising one woman with eclampsia, six women with pre-eclampsia, four women with uncomplicated normotensive pregnancies and two male relatives. The analysis of WGBS profiles using two bioinformatics platforms, BSmooth and Bismark, revealed 18,909 differentially methylated CpGs and 4157 differentially methylated regions (DMRs) concordant in females. The methylation patterns support the involvement of previously reported candidate genes, including COL4A1, SLC2A4, PER3, FLT1, GPI, LCT, DDAH1, TGFB3, DLX5, and LRP1B. Statistical analysis of DMRs revealed three novel genes significantly correlated with pre-eclampsia: sorbitol dehydrogenase (SORD, p = 9.98 x 10(-6)), diacylglycerol kinase iota (DGKI, p = 2.52 x 10(-5)), and islet cell autoantigen 1 (ICA1, 7.54 x 10(-3)), demonstrating the potential of WGBS in families for elucidating the role of epigenome in pre-eclampsia and other complex diseases.",
keywords = "epigenetics, whole-genome bisulfite sequencing (WGBS), pre-eclampsia, DGK, ICA, SORD, DNA methylation (CpG), differentially methylated region (DMR), TUMOR-NECROSIS-FACTOR, MATERNAL SUSCEPTIBILITY LOCUS, GENOME-WIDE SCAN, DNA METHYLATION, GESTATIONAL HYPERTENSION, COMPREHENSIVE ANALYSIS, CHROMOSOME 2Q22, HUMAN PLACENTAS, READ ALIGNMENT, FACTOR-ALPHA",
author = "Amir Ariff and Melton, {Phillip E.} and Brennecke, {Shaun P.} and Moses, {Eric K.}",
year = "2019",
month = "3",
day = "19",
doi = "10.3389/fgene.2019.00227",
language = "English",
volume = "10",
journal = "Frontiers in Genetics",
issn = "1664-8021",
publisher = "Frontiers Media SA",

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TY - JOUR

T1 - Analysis of the Epigenome in Multiplex Pre-eclampsia Families Identifies SORD, DGKI, and ICA1 as Novel Candidate Risk Genes

AU - Ariff, Amir

AU - Melton, Phillip E.

AU - Brennecke, Shaun P.

AU - Moses, Eric K.

PY - 2019/3/19

Y1 - 2019/3/19

N2 - Pre-eclampsia is a serious heritable disorder that affects 5-8% of pregnancies worldwide. While classical genetic studies have identified several susceptibility genes they do not fully explain the heritability of pre-eclampsia. An additional contribution to risk can be quantified by examining the epigenome, in particular the methylome, which is a representation of interactions between environmental and genetic influences on the phenotype. Current array-based epigenetic studies only examine 2-5% of the methylome. Here, we used whole-genome bisulfite sequencing (WGBS) to determine the entire methylome of 13 individuals from two multiplex pre-eclampsia families, comprising one woman with eclampsia, six women with pre-eclampsia, four women with uncomplicated normotensive pregnancies and two male relatives. The analysis of WGBS profiles using two bioinformatics platforms, BSmooth and Bismark, revealed 18,909 differentially methylated CpGs and 4157 differentially methylated regions (DMRs) concordant in females. The methylation patterns support the involvement of previously reported candidate genes, including COL4A1, SLC2A4, PER3, FLT1, GPI, LCT, DDAH1, TGFB3, DLX5, and LRP1B. Statistical analysis of DMRs revealed three novel genes significantly correlated with pre-eclampsia: sorbitol dehydrogenase (SORD, p = 9.98 x 10(-6)), diacylglycerol kinase iota (DGKI, p = 2.52 x 10(-5)), and islet cell autoantigen 1 (ICA1, 7.54 x 10(-3)), demonstrating the potential of WGBS in families for elucidating the role of epigenome in pre-eclampsia and other complex diseases.

AB - Pre-eclampsia is a serious heritable disorder that affects 5-8% of pregnancies worldwide. While classical genetic studies have identified several susceptibility genes they do not fully explain the heritability of pre-eclampsia. An additional contribution to risk can be quantified by examining the epigenome, in particular the methylome, which is a representation of interactions between environmental and genetic influences on the phenotype. Current array-based epigenetic studies only examine 2-5% of the methylome. Here, we used whole-genome bisulfite sequencing (WGBS) to determine the entire methylome of 13 individuals from two multiplex pre-eclampsia families, comprising one woman with eclampsia, six women with pre-eclampsia, four women with uncomplicated normotensive pregnancies and two male relatives. The analysis of WGBS profiles using two bioinformatics platforms, BSmooth and Bismark, revealed 18,909 differentially methylated CpGs and 4157 differentially methylated regions (DMRs) concordant in females. The methylation patterns support the involvement of previously reported candidate genes, including COL4A1, SLC2A4, PER3, FLT1, GPI, LCT, DDAH1, TGFB3, DLX5, and LRP1B. Statistical analysis of DMRs revealed three novel genes significantly correlated with pre-eclampsia: sorbitol dehydrogenase (SORD, p = 9.98 x 10(-6)), diacylglycerol kinase iota (DGKI, p = 2.52 x 10(-5)), and islet cell autoantigen 1 (ICA1, 7.54 x 10(-3)), demonstrating the potential of WGBS in families for elucidating the role of epigenome in pre-eclampsia and other complex diseases.

KW - epigenetics

KW - whole-genome bisulfite sequencing (WGBS)

KW - pre-eclampsia

KW - DGK

KW - ICA

KW - SORD

KW - DNA methylation (CpG)

KW - differentially methylated region (DMR)

KW - TUMOR-NECROSIS-FACTOR

KW - MATERNAL SUSCEPTIBILITY LOCUS

KW - GENOME-WIDE SCAN

KW - DNA METHYLATION

KW - GESTATIONAL HYPERTENSION

KW - COMPREHENSIVE ANALYSIS

KW - CHROMOSOME 2Q22

KW - HUMAN PLACENTAS

KW - READ ALIGNMENT

KW - FACTOR-ALPHA

U2 - 10.3389/fgene.2019.00227

DO - 10.3389/fgene.2019.00227

M3 - Article

VL - 10

JO - Frontiers in Genetics

JF - Frontiers in Genetics

SN - 1664-8021

M1 - 227

ER -