Periconceptional Maternal Mediterranean Diet Is Associated With Favorable Offspring Behaviors and Altered CpG Methylation of Imprinted Genes

Abstract

Background: Maternal diet during pregnancy has been shown to influence the child neuro-developmental outcomes. Studies examining effects of dietary patterns on offspring behavior are sparse. Objective: Determine if maternal adherence to a Mediterranean diet is associated with child behavioral outcomes assessed early in life, and to evaluate the role of differentially methylated regions (DMRs) regulating genomically imprinted genes in these associations. Methods: Among 325 mother/infant pairs, we used regression models to evaluate the association between tertiles of maternal periconceptional Mediterranean diet adherence (MDA) scores derived from a Food Frequency Questionnaire, and social and emotional scores derived from the Infant Toddler Social and Emotional Assessment (ITSEA) questionnaire in the second year of life. Methylation of nine genomically imprinted genes was measured to determine if MDA was associated with CpG methylation. Results: Child depression was inversely associated with maternal MDA (Bonferroni-corrected p = 0.041). While controlling for false-discovery, compared to offspring of women with the lowest MDA tertile, those with MDA scores in middle and high MDA tertiles had decreased odds for atypical behaviors [OR (95% CI) = 0.40 (0.20, 0.78) for middle and 0.40 (0.17, 0.92) for highest tertile], for maladaptive behaviors [0.37 (0.18, 0.72) for middle tertile and 0.42 (0.18, 0.95) for highest tertile] and for an index of autism spectrum disorder behaviors [0.46 (0.23, 0.90) for middle and 0.35 (0.15, 0.80) for highest tertile]. Offspring of women with the highest MDA tertile were less likely to exhibit depressive [OR = 0.28 (0.12, 0.64)] and anxiety [0.42 (0.18, 0.97)] behaviors and increased odds of social relatedness [2.31 (1.04, 5.19)] behaviors when compared to low MDA mothers. Some associations varied by sex. Perinatal MDA score was associated with methylation differences for imprinted control regions of PEG10/SGCE [females: Beta (95% CI) = 1.66 (0.52, 2.80) - Bonferroni-corrected p = 0.048; males: -0.56 (-1.13, -0.00)], as well as both MEG3 and IGF2 in males [0.97 (0.00, 1.94)] and -0.92 (-1.65, -0.19) respectively. Conclusion: In this ethnically diverse cohort, maternal adherence to a Mediterranean diet in early pregnancy was associated with favorable neurobehavioral outcomes in early childhood and with sex-dependent methylation differences of MEG3, IGF2, and SGCE/PEG10 DMRs.

Keywords: ADHD-attention deficit disorder; autism spectrum disorder; child behavior disorders; cord-blood methylation; epigenetics; imprinted genes; maternal diet; neuro-development.

FIGURE 1

Maternal Mediterranean Diet Adherence (MDA) and Child Behavior Outcomes. For a given tertile of maternal MDA compared to tertile 1 (referent), the odds ratio (95% confidence interval) represents the risk of being in a higher tertile of behavioral outcome. Unadjusted (gray) and adjusted (blue) odds ratios (95% confidence intervals) are plotted. Estimates were adjusted for breastfeeding at least 3 months, age of child at behavioral assessment, maternal fiber intake, total calories, folate, education, diabetes, obesity, smoking, and age, as well as paternal age and child parity, premature birth, weight, race, and child sex. Q-values are shown and represent the false discovery rate (FDR) for each finding, which is automatically corrected for multiple testing. ^∗Bonferroni-corrected p-trend = 0.041.

FIGURE 2

Maternal MDA and CpG Methylation. Females (light gray) and males (dark gray) were evaluated separately with linear regression for associations of maternal MDA on the average methylation status of the control region of 9 imprinted gene loci. Effect estimates for mean CpG methylation were adjusted for breastfeeding at least 3 months, age of child at behavioral assessment, maternal fiber intake, total calories, folate, education, diabetes, obesity, smoking, and age, as well as paternal age and child parity, premature birth, weight, race (^∗FDR q < 0.15; n ranged from 51 to 75).

FIGURE 3

Sex Specific Maternal MDA and CpG Associations on Child Behavior. In females (orange), maternal MDA is associated with increased methylation in the control region of SGCE/PEG10 locus. In turn, this is associated with decreased odds of depression, anxiety, atypical, and Autism Spectrum Disorder (ASD) composite index behaviors, as is maternal MDA. In males (green), maternal MDA is associated with hypo-methylation of the control region of IGF2 and SGCE/PEG10 loci and hyper-methylation of the MEG3 control region which are, in turn, are consistently associated with maternal MDA associations on atypical and social relatedness behaviors.