Newborn genome-wide DNA methylation in association with pregnancy anxiety reveals a potential role for GABBR1

Elise Beau Vangeel,Titia Hompes,Kathleen Freson,Stephan Claes,Diether Lambrechts,Benedetta Izzi,Ehsan Pishva,Karel Allegaert,Daniel Van Den Hove

doi:10.1186/s13148-017-0408-5

Abstract

BackgroundThere is increasing evidence for the role of prenatal stress in shaping offspring DNA methylation and disease susceptibility. In the current study, we aimed to identify genes and pathways associated with pregnancy anxiety using a genome-wide DNA methylation approach.MethodsWe selected 22 versus 23 newborns from our Prenatal Early Life Stress (PELS) cohort, exposed to the lowest or highest degree of maternal pregnancy anxiety, respectively. Cord blood genome-wide DNA methylation was assayed using the HumanMethylation450 BeadChip (HM450, n = 45) and candidate gene methylation using EpiTYPER (n = 80). Cortisol levels were measured at 2, 4, and 12 months of age to test infant stress system (re)activity.ResultsData showed ten differentially methylated regions (DMR) when comparing newborns exposed to low versus high pregnancy anxiety scores. We validated a top DMR in the GABA-B receptor subunit 1 gene (GABBR1) revealing the association with pregnancy anxiety particularly in male newborns (most significant CpG Pearson R = 0.517, p = 0.002; average methylation Pearson R = 0.332, p = 0.039). Cord blood GABBR1 methylation was associated with infant cortisol levels in response to a routine vaccination at 4 months old.ConclusionsIn conclusion, our results show that pregnancy anxiety is associated with differential DNA methylation patterns in newborns and that our candidate gene GABBR1 is associated with infant hypothalamic-pituitary-adrenal axis response to a stressor. Our findings reveal a potential role for GABBR1 methylation in association with stress and provide grounds for further research.

Highlights

There is increasing evidence for the role of prenatal stress in shaping offspring DNA methylation and disease susceptibility
In previous publications examining our specific birth cohort, we have shown that pregnancy anxiety appeared to be an important factor associated with DNA methylation changes of the NR3C1 gene [14] and two imprinted genes involved in fetal development, i.e., insulin-like growth factor 2 (IGF2) and guanine nucleotide binding protein, alpha stimulating (GNAS) in cord blood [15]
To select the samples for epigenome-wide association studies (EWAS), we focused on the fear of integrity subscale of pregnancy-related anxiety questionnaire (PRAQ), which appeared as most associated with DNA methylation in our candidate gene studies [14, 15]

Summary

Introduction

There is increasing evidence for the role of prenatal stress in shaping offspring DNA methylation and disease susceptibility. We aimed to identify genes and pathways associated with pregnancy anxiety using a genome-wide DNA methylation approach. Vangeel et al Clinical Epigenetics (2017) 9:107 in HPA axis [6, 9] or immune system function [10] was associated with prenatal stress as well In addition to these candidate gene approaches, some epigenome-wide association studies (EWAS) have examined the potential role of prenatal stress. Genome-wide DNA methylation changes have been found in newborns from women with non-medicated depression or anxiety during pregnancy [11], while another study shows an association between the methyltransferase pathway and prenatal stress in two population-based cohorts [12]. A recent study by Serpeloni et al described genome-wide DNA methylation changes associated with grandmaternal exposure to violence during pregnancy [13]

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