title: Preliminary assessment of pre-morbid DNA methylation in individuals at high genetic risk of mood disorders.
abstract: Accumulating evidence implicates altered DNA methylation in psychiatric disorders, including bipolar disorder (BD) and major depressive disorder (MDD). It is not clear, however, whether these changes are causative or result from illness progression or treatment. To disentangle these possibilities we profiled genome-wide DNA methylation in well, unrelated individuals at high familial risk of mood disorder. DNA methylation was compared between individuals who subsequently developed BD or MDD [ill later (IL)] and those who remained well [well later (WL)].
  
  
  
  DNA methylation profiles were obtained from whole-blood samples from 22 IL and 23 WL individuals using the Infinium HumanMethylation450 BeadChip. Differential methylation was assessed on a single-locus and regional basis. Pathway analysis was performed to assess enrichment for particular biological processes amongst nominally significantly differentially methylated loci.
  
  
  
  Although no locus withstood correction for multiple testing, uncorrected P-values provided suggestive evidence for altered methylation at sites within genes previously implicated in neuropsychiatric conditions, such as Transcription Factor 4 (TCF4) and Interleukin 1 Receptor Accessory Protein-Like 1 ([IL1RAPL1]; P≤3.11×10(-5) ). Pathway analysis revealed significant enrichment for several neurologically relevant pathways and functions, including Nervous System Development and Function and Behavior; these findings withstood multiple testing correction (q≤0.05). Analysis of differentially methylated regions identified several within the major histocompatibility complex (P≤.000 479), a region previously implicated in schizophrenia and BD.
  
  
  
  Our data provide provisional evidence for the involvement of altered whole-blood DNA methylation in neurologically relevant genes in the aetiology of mood disorders. These findings are convergent with the findings of genome-wide association studies.
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors.forename: Rosie May
authors.initials: RM
authors.lastname: Walker
authors.affiliation: Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
authors.forename: Jessika Elizabeth
authors.initials: JE
authors.lastname: Sussmann
authors.affiliation: Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
authors.forename: Heather Clare
authors.initials: HC
authors.lastname: Whalley
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors.forename: Niamh Margaret
authors.initials: NM
authors.lastname: Ryan
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
authors.forename: David John
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
authors.forename: Andrew Mark
authors.initials: AM
authors.lastname: McIntosh
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
authors.forename: Kathryn Louise
authors.initials: KL
authors.lastname: Evans
mesh_terms: D000328:Adult; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics*; D019175:DNA Methylation / Q000502:physiology*; D003865:Major Depressive Disorder / Q000235:genetics*; D005260:Female; D006801:Humans; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics*; D008297:Male; D012307:Risk Factors; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C407643:IL1RAPL1 protein, human; D053577:Interleukin-1 Receptor Accessory Protein; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors
keywords: 450K array; DNA methylation; Interleukin 1 Receptor Accessory Protein-Like 1; Transcription Factor 4; bipolar disorder; major depressive disorder; premorbid