Association between perinatal methylation of the neuronal differentiation regulator HES1 and later childhood neurocognitive function and behaviour

• Published in: International journal of epidemiology Vol. 44; no. 4; pp. 1263 - 1276
• Main Authors: Lillycrop, Karen A, Costello, Paula M, Teh, Ai Ling, Murray, Robert J, Clarke-Harris, Rebecca, Barton, Sheila J, Garratt, Emma S, Ngo, Sherry, Sheppard, Allan M, Wong, Johnny, Dogra, Shaillay, Burdge, Graham C, Cooper, Cyrus, Inskip, Hazel M, Gale, Catharine R, Gluckman, Peter D, Harvey, Nicholas C, Chong, Yap-Seng, Yap, Fabian, Meaney, Michael J, Rifkin-Graboi, Anne, Holbrook, Joanna D, Godfrey, Keith M
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.08.2015
• Subjects: Adult; Basic Helix-Loop-Helix Transcription Factors - genetics; Child; Child Behavior - psychology; Child, Preschool; Cognition; DNA Methylation; Early Life Environment; Epigenesis, Genetic; Female; Homeodomain Proteins - genetics; Humans; Male; Pregnancy; Promoter Regions, Genetic; Prospective Studies; Regression Analysis; Transcription Factor HES-1; HES1; epigenetic; methylation; perinatal; neurocognitive development
• ISSN: 0300-5771; 1464-3685
• DOI: 10.1093/ije/dyv052

Early life environments induce long-term changes in neurocognitive development and behaviour. In animal models, early environmental cues affect neuropsychological phenotypes via epigenetic processes but, as yet, there is little direct evidence for such mechanisms in humans. We examined the relation between DNA methylation at birth and child neuropsychological outcomes in two culturally diverse populations using a genome-wide methylation analysis and validation by pyrosequencing. Within the UK Southampton Women's Survey (SWS) we first identified 41 differentially methylated regions of interest (DMROI) at birth associated with child's full-scale IQ at age 4 years. Associations between HES1 DMROI methylation and later cognitive function were confirmed by pyrosequencing in 175 SWS children. Consistent with these findings, higher HES1 methylation was associated with higher executive memory function in a second independent group of 200 SWS 7-year-olds. Finally, we examined a pathway for this relationship within a Singaporean cohort (n = 108). Here, HES1 DMROI methylation predicted differences in early infant behaviour, known to be associated with academic success. In vitro, methylation of HES1 inhibited ETS transcription factor binding, suggesting a functional role of this site. Thus, our findings suggest that perinatal epigenetic processes mark later neurocognitive function and behaviour, providing support for a role of epigenetic processes in mediating the long-term consequences of early life environment on cognitive development.