title: DNA modification study of major depressive disorder: beyond locus-by-locus comparisons.
abstract: BACKGROUND
  Major depressive disorder (MDD) exhibits numerous clinical and molecular features that are consistent with putative epigenetic misregulation. Despite growing interest in epigenetic studies of psychiatric diseases, the methodologies guiding such studies have not been well defined.
  
  
  METHODS
  We performed DNA modification analysis in white blood cells from monozygotic twins discordant for MDD, in brain prefrontal cortex, and germline (sperm) samples from affected individuals and control subjects (total N = 304) using 8.1K CpG island microarrays and fine mapping. In addition to the traditional locus-by-locus comparisons, we explored the potential of new analytical approaches in epigenomic studies.
  
  
  RESULTS
  In the microarray experiment, we detected a number of nominally significant DNA modification differences in MDD and validated selected targets using bisulfite pyrosequencing. Some MDD epigenetic changes, however, overlapped across brain, blood, and sperm more often than expected by chance. We also demonstrated that stratification for disease severity and age may increase the statistical power of epimutation detection. Finally, a series of new analytical approaches, such as DNA modification networks and machine-learning algorithms using binary and quantitative depression phenotypes, provided additional insights on the epigenetic contributions to MDD.
  
  
  CONCLUSIONS
  Mapping epigenetic differences in MDD (and other psychiatric diseases) is a complex task. However, combining traditional and innovative analytical strategies may lead to identification of disease-specific etiopathogenic epimutations.
authors.affiliation: Krembil Family Epigenetics Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Institute of Systems Biology and Bioinformatics, National Central University, Chungli, Taiwan.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Oh
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Chungli, Taiwan; Department of Public Health Sciences, Dalla Lana School of Public Health, Toronto, Ontario, Canada.
authors.forename: Sun-Chong
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Chungli, Taiwan.
authors.forename: Mrinal
authors.initials: M
authors.lastname: Pal
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Zheng Fei
authors.initials: ZF
authors.lastname: Chen
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Chungli, Taiwan.
authors.forename: Tarang
authors.initials: T
authors.lastname: Khare
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Chungli, Taiwan; Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tochigi
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Chungli, Taiwan.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ng
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Chungli, Taiwan; Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore Maryland.
authors.forename: Yeqing A
authors.initials: YA
authors.lastname: Yang
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Chungli, Taiwan.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kwan
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Chungli, Taiwan; Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King׳s College, London, United Kingdom.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Kaminsky
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Chungli, Taiwan; Department of Psychology, University of Houston, Houston, Texas.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.affiliation: Department of Psychology, University of Houston, Houston, Texas; University of Exeter Medical School, Exeter University, Exeter, United Kingdom.
authors.forename: Cerisse
authors.initials: C
authors.lastname: Gunasinghe
authors.affiliation: Departments of Psychology and Psychiatry, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Tackett
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Netherlands Twin Register.
authors.forename: Irving I
authors.initials: II
authors.lastname: Gottesman
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, The Netherlands.
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, The Netherlands.
authors.forename: Eco J C
authors.initials: EJC
authors.lastname: de Geus
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, The Netherlands.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Vink
authors.affiliation: Queensland Institute of Medical Research, Herston.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: The Queensland Brain Institute, University of Queensland, St Lucia, Australia; Department of Psychiatry, Washington University in St Louis, St Louis, Missouri.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.affiliation: The Queensland Brain Institute, University of Queensland, St Lucia, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: Department of Psychiatry, McGill University, Montreal, Quebec, Canada; National Institute for Health Research Biomedical Research Centre for Mental Health at South London and Maudsley National Health Service Foundation Trust, London.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.affiliation: The Queensland Brain Institute, University of Queensland, St Lucia, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Department of Psychology, University of Houston, Houston, Texas; University of Exeter Medical School, Exeter University, Exeter, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Rafal
authors.initials: R
authors.lastname: Kustra
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Chungli, Taiwan. Electronic address: art.petronis@camh.ca.
authors.forename: Art
authors.initials: A
authors.lastname: Petronis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018899:CpG Islands; D003865:Major Depressive Disorder / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007962:Leukocytes; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D017397:Prefrontal Cortex; D013094:Spermatozoa; D014430:Twins, Monozygotic; D055815:Young Adult
keywords: DNA modification; Epigenetic outliers; Epigenetics; Heteroscedasticity; Major depressive disorder; Molecular networks
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