Maternal prenatal anxiety and child COMT genotype predict working memory and symptoms of ADHD.

Kieran J O'Donnell,Marius Lahti,Jari Lahti,Katri Räikkönen,Thomas G O'Connor,Vivette Glover,Rachel D Edgar,Jodi Pawluski

doi:10.1371/journal.pone.0177506

Abstract

Maternal prenatal anxiety is an important risk factor for altered child neurodevelopment but there is uncertainty concerning the biological mechanisms involved and sources of individual differences in children’s responses. We sought to determine the role of functional genetic variation in COMT, which encodes catechol-O-methyltransferase, in the association between maternal prenatal anxiety and child symptoms of ADHD and working memory. We used the prospectively-designed ALSPAC cohort (n = 6,969) for our primary data analyses followed by replication analyses in the PREDO cohort (n = 425). Maternal prenatal anxiety was based on self-report measures; child symptoms of ADHD were collected from 4–15 years of age; working memory was assessed from in-person testing at age 8 years; and genetic variation in COMT at rs4680 was determined in both mothers and children. The association between maternal prenatal anxiety and child attention/hyperactivity symptoms and working memory was moderated by the child’s rs4680 genotype, with stronger effects obtained for the val/val (G:G) genotype relative to val/met (A:G) (all p<0.01) and met/met (A:A) groups (all p<0.05). Similar findings were observed in the PREDO cohort where maternal prenatal anxiety interacted with child rs4680 to predict symptoms of ADHD at 3.5 years of age. The findings, from two cohorts, show a robust gene-environment interaction, which may contribute to inter-individual differences in the effects of maternal prenatal anxiety on developmental outcomes from childhood to mid-adolescence.

Highlights

There is a sizable evidence base from research groups in several countries linking psychological distress in pregnancy with altered neurodevelopment—cognitive and intellectual abilities, executive functions, language, and brain imaging—in the children, adolescents and young adults [1,2,3,4,5,6,7,8,9,10]
Our focus is on COMT because it has a clear link with neurodevelopment and has been investigated in prior work on genetic moderation, but we include, for exploratory purposes, analyses of BDNF, which we have previously shown to moderate maternal prenatal anxiety in predicting child emotional problems [36]
Our finding that the prenatal maternal anxiety effect is moderated by child rs4680 that regulates COMT, which is involved in the inactivation of catecholamine neurotransmitters, implies that a broader biological model for understanding prenatal maternal anxiety effects is needed

Summary

Introduction

There is a sizable evidence base from research groups in several countries linking psychological distress in pregnancy with altered neurodevelopment—cognitive and intellectual abilities, executive functions, language, and brain imaging—in the children, adolescents and young adults [1,2,3,4,5,6,7,8,9,10]. These findings provide leads in identifying mechanisms of brain development, highlight the significance of prenatal exposures for child neurodevelopment, and expand the public health implications of maternal prenatal distress for the mother and child. Knickmeyer and colleagues reported reduced volume in the temporal cortex associated with the val/val homozygote in their study of newborns [15]

Methods

Results

Conclusion