title: DNA methylation of the serotonin transporter gene (SLC6A4) is associated with brain function involved in processing emotional stimuli.
abstract: BACKGROUND
  The aim of the present study was to investigate the association of fMRI blood oxygen-level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD).
  
  
  METHODS
  We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyrosequencing.
  
  
  RESULTS
  Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation.
  
  
  CONCLUSIONS
  It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn.
  
  
  CONCLUSIONS
  Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery.
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Ireland (Frodl, Carballedo, Morris, Gill); Institute of Neuroscience, University of Dublin, Trinity College Dublin, Ireland (Frodl, Gill); Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (Frodl); Centre of Advanced Medical Imaging, St. James's Hospital & Trinity College Dublin, Ireland (Frodl, Meaney); Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada (Szyf, Ly, Dymov, Vaisheva); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, University of Dublin, Trinity College Dublin, Ireland ( Fahey, Gill); Department of Psychology and Psychiatry, Queen's University, Kingston, Canada (Booij); Sainte-Justine Hospital Research Center and Université de Montréal, Montréal, Canada (Booij); Department of Psychiatry, McGill University, Montréal, Canada (Booij).
authors.forename: Thomas
authors.initials: T
authors.lastname: Frodl
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Ireland (Frodl, Carballedo, Morris, Gill); Institute of Neuroscience, University of Dublin, Trinity College Dublin, Ireland (Frodl, Gill); Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (Frodl); Centre of Advanced Medical Imaging, St. James's Hospital & Trinity College Dublin, Ireland (Frodl, Meaney); Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada (Szyf, Ly, Dymov, Vaisheva); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, University of Dublin, Trinity College Dublin, Ireland ( Fahey, Gill); Department of Psychology and Psychiatry, Queen's University, Kingston, Canada (Booij); Sainte-Justine Hospital Research Center and Université de Montréal, Montréal, Canada (Booij); Department of Psychiatry, McGill University, Montréal, Canada (Booij).
authors.forename: Moshe
authors.initials: M
authors.lastname: Szyf
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Ireland (Frodl, Carballedo, Morris, Gill); Institute of Neuroscience, University of Dublin, Trinity College Dublin, Ireland (Frodl, Gill); Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (Frodl); Centre of Advanced Medical Imaging, St. James's Hospital & Trinity College Dublin, Ireland (Frodl, Meaney); Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada (Szyf, Ly, Dymov, Vaisheva); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, University of Dublin, Trinity College Dublin, Ireland ( Fahey, Gill); Department of Psychology and Psychiatry, Queen's University, Kingston, Canada (Booij); Sainte-Justine Hospital Research Center and Université de Montréal, Montréal, Canada (Booij); Department of Psychiatry, McGill University, Montréal, Canada (Booij).
authors.forename: Angela
authors.initials: A
authors.lastname: Carballedo
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Ireland (Frodl, Carballedo, Morris, Gill); Institute of Neuroscience, University of Dublin, Trinity College Dublin, Ireland (Frodl, Gill); Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (Frodl); Centre of Advanced Medical Imaging, St. James's Hospital & Trinity College Dublin, Ireland (Frodl, Meaney); Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada (Szyf, Ly, Dymov, Vaisheva); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, University of Dublin, Trinity College Dublin, Ireland ( Fahey, Gill); Department of Psychology and Psychiatry, Queen's University, Kingston, Canada (Booij); Sainte-Justine Hospital Research Center and Université de Montréal, Montréal, Canada (Booij); Department of Psychiatry, McGill University, Montréal, Canada (Booij).
authors.forename: Victoria
authors.initials: V
authors.lastname: Ly
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Ireland (Frodl, Carballedo, Morris, Gill); Institute of Neuroscience, University of Dublin, Trinity College Dublin, Ireland (Frodl, Gill); Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (Frodl); Centre of Advanced Medical Imaging, St. James's Hospital & Trinity College Dublin, Ireland (Frodl, Meaney); Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada (Szyf, Ly, Dymov, Vaisheva); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, University of Dublin, Trinity College Dublin, Ireland ( Fahey, Gill); Department of Psychology and Psychiatry, Queen's University, Kingston, Canada (Booij); Sainte-Justine Hospital Research Center and Université de Montréal, Montréal, Canada (Booij); Department of Psychiatry, McGill University, Montréal, Canada (Booij).
authors.forename: Sergiy
authors.initials: S
authors.lastname: Dymov
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Ireland (Frodl, Carballedo, Morris, Gill); Institute of Neuroscience, University of Dublin, Trinity College Dublin, Ireland (Frodl, Gill); Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (Frodl); Centre of Advanced Medical Imaging, St. James's Hospital & Trinity College Dublin, Ireland (Frodl, Meaney); Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada (Szyf, Ly, Dymov, Vaisheva); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, University of Dublin, Trinity College Dublin, Ireland ( Fahey, Gill); Department of Psychology and Psychiatry, Queen's University, Kingston, Canada (Booij); Sainte-Justine Hospital Research Center and Université de Montréal, Montréal, Canada (Booij); Department of Psychiatry, McGill University, Montréal, Canada (Booij).
authors.forename: Farida
authors.initials: F
authors.lastname: Vaisheva
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Ireland (Frodl, Carballedo, Morris, Gill); Institute of Neuroscience, University of Dublin, Trinity College Dublin, Ireland (Frodl, Gill); Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (Frodl); Centre of Advanced Medical Imaging, St. James's Hospital & Trinity College Dublin, Ireland (Frodl, Meaney); Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada (Szyf, Ly, Dymov, Vaisheva); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, University of Dublin, Trinity College Dublin, Ireland ( Fahey, Gill); Department of Psychology and Psychiatry, Queen's University, Kingston, Canada (Booij); Sainte-Justine Hospital Research Center and Université de Montréal, Montréal, Canada (Booij); Department of Psychiatry, McGill University, Montréal, Canada (Booij).
authors.forename: Derek
authors.initials: D
authors.lastname: Morris
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Ireland (Frodl, Carballedo, Morris, Gill); Institute of Neuroscience, University of Dublin, Trinity College Dublin, Ireland (Frodl, Gill); Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (Frodl); Centre of Advanced Medical Imaging, St. James's Hospital & Trinity College Dublin, Ireland (Frodl, Meaney); Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada (Szyf, Ly, Dymov, Vaisheva); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, University of Dublin, Trinity College Dublin, Ireland ( Fahey, Gill); Department of Psychology and Psychiatry, Queen's University, Kingston, Canada (Booij); Sainte-Justine Hospital Research Center and Université de Montréal, Montréal, Canada (Booij); Department of Psychiatry, McGill University, Montréal, Canada (Booij).
authors.forename: Ciara
authors.initials: C
authors.lastname: Fahey
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Ireland (Frodl, Carballedo, Morris, Gill); Institute of Neuroscience, University of Dublin, Trinity College Dublin, Ireland (Frodl, Gill); Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (Frodl); Centre of Advanced Medical Imaging, St. James's Hospital & Trinity College Dublin, Ireland (Frodl, Meaney); Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada (Szyf, Ly, Dymov, Vaisheva); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, University of Dublin, Trinity College Dublin, Ireland ( Fahey, Gill); Department of Psychology and Psychiatry, Queen's University, Kingston, Canada (Booij); Sainte-Justine Hospital Research Center and Université de Montréal, Montréal, Canada (Booij); Department of Psychiatry, McGill University, Montréal, Canada (Booij).
authors.forename: James
authors.initials: J
authors.lastname: Meaney
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Ireland (Frodl, Carballedo, Morris, Gill); Institute of Neuroscience, University of Dublin, Trinity College Dublin, Ireland (Frodl, Gill); Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (Frodl); Centre of Advanced Medical Imaging, St. James's Hospital & Trinity College Dublin, Ireland (Frodl, Meaney); Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada (Szyf, Ly, Dymov, Vaisheva); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, University of Dublin, Trinity College Dublin, Ireland ( Fahey, Gill); Department of Psychology and Psychiatry, Queen's University, Kingston, Canada (Booij); Sainte-Justine Hospital Research Center and Université de Montréal, Montréal, Canada (Booij); Department of Psychiatry, McGill University, Montréal, Canada (Booij).
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.affiliation: Department of Psychiatry, University of Dublin, Trinity College Dublin, Ireland (Frodl, Carballedo, Morris, Gill); Institute of Neuroscience, University of Dublin, Trinity College Dublin, Ireland (Frodl, Gill); Department of Psychiatry and Psychotherapy, University of Regensburg, Germany (Frodl); Centre of Advanced Medical Imaging, St. James's Hospital & Trinity College Dublin, Ireland (Frodl, Meaney); Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada (Szyf, Ly, Dymov, Vaisheva); Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, University of Dublin, Trinity College Dublin, Ireland ( Fahey, Gill); Department of Psychology and Psychiatry, Queen's University, Kingston, Canada (Booij); Sainte-Justine Hospital Research Center and Université de Montréal, Montréal, Canada (Booij); Department of Psychiatry, McGill University, Montréal, Canada (Booij).
authors.forename: Linda
authors.initials: L
authors.lastname: Booij
mesh_terms: D000328:Adult; D001923:Brain Chemistry / Q000235:genetics*; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D004644:Emotions; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D050486:Serotonin Plasma Membrane Transport Proteins / Q000097:blood / Q000235:genetics*; D055815:Young Adult
chemical_list: C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins
references.citation: Neuroreport. 2003 May 6;14(6):791-7
references.pmid: 12858034
references.citation: Curr Neuropharmacol. 2006 Apr;4(2):101-14
references.pmid: 18615128
references.citation: Nat Neurosci. 2014 Sep;17(9):1153-5
references.pmid: 25086606
references.citation: Am J Psychiatry. 1999 May;156(5):675-82
references.pmid: 10327898
references.citation: Psychiatr Neurol Neurochir. 1969 Mar-Apr;72(2):201-5
references.pmid: 5792061
references.citation: Science. 2002 Jul 19;297(5580):400-3
references.pmid: 12130784
references.citation: Neuropsychopharmacology. 2008 Jan;33(2):418-24
references.pmid: 17406646
references.citation: Psychosom Med. 2011 Jan;73(1):83-7
references.pmid: 20947778
references.citation: Nat Rev Neurosci. 2009 Jan;10(1):59-70
references.pmid: 19096369
references.citation: J Psychiatr Res. 2012 Feb;46(2):181-8
references.pmid: 22078646
references.citation: Neuroimage. 2007 Feb 15;34(4):1744-53
references.pmid: 17175173
references.citation: Neuroimage. 2006 May 1;30(4):1441-8
references.pmid: 16368249
references.citation: Science. 1996 Nov 1;274(5288):740-3
references.pmid: 8966556
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):710-3
references.pmid: 19739105
references.citation: Am J Psychiatry. 1994 Aug;151(8):1132-6
references.pmid: 8037246
references.citation: Nat Neurosci. 2000 Oct;3(10):1049-56
references.pmid: 11017179
references.citation: J Comp Neurol. 2013 Oct 15;521(15):3371-88
references.pmid: 23749500
references.citation: Nature. 2008 Oct 16;455(7215):894-902
references.pmid: 18923511
references.citation: J Affect Disord. 2011 Apr;130(1-2):66-74
references.pmid: 21030092
references.citation: Neuron. 2003 Oct 30;40(3):655-64
references.pmid: 14642287
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jul 1;44:23-8
references.pmid: 23333376
references.citation: Neuroreport. 2007 Aug 27;18(13):1351-5
references.pmid: 17762711
references.citation: J Occup Environ Med. 2003 Jan;45(1):5-14
references.pmid: 12553174
references.citation: Arch Gen Psychiatry. 1992 Aug;49(8):624-9
references.pmid: 1637252
references.citation: Neuropsychopharmacology. 2010 May;35(6):1383-90
references.pmid: 20147891
references.citation: J Neurosci. 2011 May 4;31(18):6692-8
references.pmid: 21543598
references.citation: Soc Cogn Affect Neurosci. 2014 Dec;9(12):2026-33
references.pmid: 24493840
references.citation: Mol Psychiatry. 2013 Apr;18(4):512-20
references.pmid: 22488255
references.citation: PLoS One. 2010;5(8):e12201
references.pmid: 20808944
references.citation: PLoS One. 2013;8(8):e71691
references.pmid: 23977113
references.citation: Hum Brain Mapp. 2013 Nov;34(11):2899-909
references.pmid: 22696400
references.citation: PLoS One. 2012;7(6):e39501
references.pmid: 22745770
references.citation: Neuroimage. 2010 Nov 15;53(3):810-21
references.pmid: 20156570
references.citation: Child Abuse Negl. 2003 Feb;27(2):169-90
references.pmid: 12615092
references.citation: J Psychiatry Neurosci. 2015 Jan;40(1):5-18
references.pmid: 25285876
references.citation: Mol Psychiatry. 2011 Jun;16(6):604-19
references.pmid: 21602829
references.citation: Neuroimage. 2010 Jan 1;49(1):939-46
references.pmid: 19699306
references.citation: Psychopharmacology (Berl). 2008 Mar;196(4):661-72
references.pmid: 18058090
references.citation: Genome Biol. 2012;13(6):R43
references.pmid: 22703893
references.citation: Psychiatry Res. 2004 Sep 30;128(2):123-33
references.pmid: 15488955
references.citation: JAMA Psychiatry. 2014 Apr;71(4):454-6
references.pmid: 24499927
references.citation: Philos Trans R Soc Lond B Biol Sci. 2013;368(1615):20120251
references.pmid: 23440465
references.citation: Trends Cogn Sci. 2009 Aug;13(8):334-40
references.pmid: 19643659
references.citation: J Affect Disord. 2013 Nov;151(2):423-31
references.pmid: 23890584
references.citation: Hum Brain Mapp. 2014 Nov;35(11):5356-67
references.pmid: 24862560
references.citation: Br J Psychiatry. 2013 Apr;202(4):269-76
references.pmid: 23470285