title: DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder.
abstract: BACKGROUND
  Bipolar disorder (BD) is a severe, familial psychiatric condition. Progress in understanding the aetiology of BD has been hampered by substantial phenotypic and genetic heterogeneity. We sought to mitigate these confounders by studying a multi-generational family multiply affected by BD and major depressive disorder (MDD), who carry an illness-linked haplotype on chromosome 4p. Within a family, aetiological heterogeneity is likely to be reduced, thus conferring greater power to detect illness-related changes. As accumulating evidence suggests that altered DNA methylation confers risk for BD and MDD, we compared genome-wide methylation between (i) affected carriers of the linked haplotype (ALH) and married-in controls (MIs), (ii) well unaffected haplotype carriers (ULH) and MI, (iii) ALH and ULH and (iv) all haplotype carriers (LH) and MI.
  
  
  RESULTS
  Nominally significant differences in DNA methylation were observed in all comparisons, with differences withstanding correction for multiple testing when the ALH or LH group was compared to the MIs. In both comparisons, we observed increased methylation at a locus in FANCI, which was accompanied by increased FANCI expression in the ALH group. FANCI is part of the Fanconi anaemia complementation (FANC) gene family, which are mutated in Fanconi anaemia and participate in DNA repair. Interestingly, several FANC genes have been implicated in psychiatric disorders. Regional analyses of methylation differences identified loci implicated in psychiatric illness by genome-wide association studies, including CACNB2 and the major histocompatibility complex. Gene ontology analysis revealed enrichment for methylation differences in neurologically relevant genes.
  
  
  CONCLUSIONS
  Our results highlight altered DNA methylation as a potential mechanism by which the linked haplotype might confer risk for mood disorders. Differences in the phenotypic outcome of haplotype carriers might, in part, arise from additional changes in DNA methylation that converge on neurologically important pathways. Further work is required to investigate the underlying mechanisms and functional consequences of the observed differences in methylation.
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU UK.
authors.forename: Rosie May
authors.initials: RM
authors.lastname: Walker
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU UK.
authors.forename: Andrea Nikie
authors.initials: AN
authors.lastname: Christoforou
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU UK.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: McCartney
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU UK.
authors.forename: Stewart W
authors.initials: SW
authors.lastname: Morris
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU UK.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Kennedy
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Morten
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU UK.
authors.forename: Susan Maguire
authors.initials: SM
authors.lastname: Anderson
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU UK.
authors.forename: Helen Scott
authors.initials: HS
authors.lastname: Torrance
authors.affiliation: Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
authors.forename: Alix
authors.initials: A
authors.lastname: Macdonald
authors.affiliation: Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
authors.forename: Jessika Elizabeth
authors.initials: JE
authors.lastname: Sussmann
authors.affiliation: Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
authors.forename: Heather Clare
authors.initials: HC
authors.lastname: Whalley
authors.affiliation: Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
authors.forename: Douglas H R
authors.initials: DH
authors.lastname: Blackwood
authors.affiliation: Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK ; Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ 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, Crewe Road, Edinburgh, EH4 2XU UK ; Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ UK.
authors.forename: David John
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU UK ; Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ UK.
authors.forename: Kathryn Louise
authors.initials: KL
authors.lastname: Evans
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000235:genetics*; D005190:Family; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics; D005260:Female; D063990:Gene Ontology; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D012606:Scotland
chemical_list: C519921:FANCI protein, human; D051856:Fanconi Anemia Complementation Group Proteins
keywords: 450K array; Bipolar disorder; DNA methylation; FANCI; Family study; Gene ontology analysis; Major depressive disorder