title: DNA methylation signature of human fetal alcohol spectrum disorder.
abstract: BACKGROUND
  Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of alcohol's effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date.
  
  
  METHODS
  Genome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip.
  
  
  RESULTS
  After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders.
  
  
  CONCLUSIONS
  These findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.
authors.affiliation: Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC Canada.
authors.forename: Elodie
authors.initials: E
authors.lastname: Portales-Casamar
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC Canada.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Lussier
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC Canada.
authors.forename: Meaghan J
authors.initials: MJ
authors.lastname: Jones
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC Canada.
authors.forename: Julia L
authors.initials: JL
authors.lastname: MacIsaac
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC Canada.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Edgar
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC Canada.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Mah
authors.affiliation: Beaulieu-Saucier Pharmacogenomics Centre, Montreal Heart Institute, Université de Montréal, Montreal, QC Canada.
authors.forename: Amina
authors.initials: A
authors.lastname: Barhdadi
authors.affiliation: Beaulieu-Saucier Pharmacogenomics Centre, Montreal Heart Institute, Université de Montréal, Montreal, QC Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Provost
authors.affiliation: Beaulieu-Saucier Pharmacogenomics Centre, Montreal Heart Institute, Université de Montréal, Montreal, QC Canada.
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Lemieux-Perreault
authors.affiliation: Brain Research Centre, University of British Columbia, Vancouver, BC Canada.
authors.forename: Max S
authors.initials: MS
authors.lastname: Cynader
authors.affiliation: Department of Pediatrics and Child Health, Faculty of Medicine, University of Manitoba, Winnipeg, MB Canada.|Department of Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, MB Canada.
authors.forename: Albert E
authors.initials: AE
authors.lastname: Chudley
authors.affiliation: Beaulieu-Saucier Pharmacogenomics Centre, Montreal Heart Institute, Université de Montréal, Montreal, QC Canada.|Faculty of Medicine, Université de Montréal, Montreal, QC Canada.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.affiliation: Centre for Neuroscience Studies, Queen's University, Kingston, ON Canada.
authors.forename: James N
authors.initials: JN
authors.lastname: Reynolds
authors.affiliation: Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Pavlidis
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC Canada.|Human Early Learning Partnership, School of Population and Public Health, University of British Columbia, Vancouver, British Columbia Canada.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kobor