title: Association between perinatal methylation of the neuronal differentiation regulator HES1 and later childhood neurocognitive function and behaviour.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Biological Sciences, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK, kal@soton.ac.uk.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Lillycrop
authors.affiliation: Academic Unit of Human Development and Health, University of Southampton, Southampton, UK.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Costello
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore.
authors.forename: Ai Ling
authors.initials: AL
authors.lastname: Teh
authors.affiliation: Academic Unit of Human Development and Health, University of Southampton, Southampton, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Murray
authors.affiliation: Academic Unit of Human Development and Health, University of Southampton, Southampton, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Clarke-Harris
authors.affiliation: MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors.forename: Sheila J
authors.initials: SJ
authors.lastname: Barton
authors.affiliation: Academic Unit of Human Development and Health, University of Southampton, Southampton, UK.
authors.forename: Emma S
authors.initials: ES
authors.lastname: Garratt
authors.affiliation: Liggins Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Sherry
authors.initials: S
authors.lastname: Ngo
authors.affiliation: Liggins Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Allan M
authors.initials: AM
authors.lastname: Sheppard
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore.
authors.forename: Johnny
authors.initials: J
authors.lastname: Wong
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore.
authors.forename: Shaillay
authors.initials: S
authors.lastname: Dogra
authors.affiliation: Academic Unit of Human Development and Health, University of Southampton, Southampton, UK.
authors.forename: Graham C
authors.initials: GC
authors.lastname: Burdge
authors.affiliation: MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK, NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK, NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Cooper
authors.affiliation: MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Inskip
authors.affiliation: MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK, Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: Catharine R
authors.initials: CR
authors.lastname: Gale
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore, Liggins Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gluckman
authors.affiliation: MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Harvey
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yap-Seng
authors.initials: YS
authors.lastname: Chong
authors.affiliation: Department of Paediatrics, KK Women's and Children's Hospital, Singapore, Duke NUS Graduate School of Medicine, National University of Singapore, Singapore, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore and.
authors.forename: Fabian
authors.initials: F
authors.lastname: Yap
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore, Ludmer Centre for Neuroinformatics and Mental Health, McGill University, Montréal, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Meaney
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore.
authors.forename: Anne
authors.initials: A
authors.lastname: Rifkin-Graboi
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore.
authors.forename: Joanna D
authors.initials: JD
authors.lastname: Holbrook
authors.affiliation: MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK, NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Godfrey
mesh_terms: D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002648:Child; D002652:Child Behavior / Q000523:psychology*; D002675:Child, Preschool; D003071:Cognition; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D012044:Regression Analysis; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human
keywords: HES1; epigenetic; methylation; neurocognitive development; perinatal