DNA Modification Study of Major Depressive Disorder: Beyond Locus-by-Locus Comparisons
Open accessAbstract
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.
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- Authors
- Oh, G., Wang, S.-C., Pal, M., Chen, Z. F., Khare, T., Tochigi, M., Ng, C., Yang, Y. A., Kwan, A., Kaminsky, Z. A., Mill, J., Gunasinghe, C., Tackett, J. L., Gottesman, I. I., Willemsen, G., de Geus, E. J. C., Vink, J. M., Slagboom, P. E., Wray, N. R., Heath, A. C., Montgomery, G. W., Turecki, G., Martin, N. G., Boomsma, D. I., McGuffin, P., Kustra, R., & Petronis, A.
- Affiliations
- Centre for Addiction and Mental Health (CA)
- University of Toronto (CA)
- National Central University (TW)
- The University of Tokyo (JP)
- Northwestern University (US)
- Johns Hopkins University (US)
- King's College London (GB)
- University of Exeter (GB)
- University of Minnesota (US)
- Vrije Universiteit Amsterdam (NL)
- Leiden University Medical Center (NL)
- QIMR Berghofer Medical Research Institute (AU)
- The University of Queensland (AU)
- Douglas Mental Health University Institute (CA)
- National Health Service (GB)
- ORCID
- Oh, Gabriel
- Pal, Mrinal
- Tochigi, Mamoru
- Yang, Yeqing A.
- Kaminsky, Zachary A.
- Mill, Jonathan
- Gunasinghe, Cerisse
- Tackett, Jennifer L.
- Gottesman, Irving I.
- Willemsen, Gonneke
- de Geus, Eco J.C.
- Vink, Jacqueline M.
- Slagboom, P. Eline
- Wray, Naomi R.
- Heath, Andrew C.
- Montgomery, Grant W.
- Turecki, Gustavo
- Martin, Nicholas G.
- Boomsma, Dorret I.
- McGuffin, Peter
- Kustra, Rafal
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 77
- Issue
- 3
- Pages
- 246-255
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4277915
- OpenAlex
- W2125955712
- Cited by
- 66
- References
- 79
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 6 · 2020: 4 · 2019: 6 · 2018: 13 · 2017: 16 · 2016: 4 · 2015: 6 · 2014: 1
- FWCI
- 3.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biological Psychiatry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- eScholarship@McGill (McGill) (submittedVersion, cc-by-nc-nd)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- VU Research Portal (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Canadian Institutes of Health Research (CIHR) (77689)
- US National Institutes of Health (MH074127, MH088413)
- National Institutes of Health (AA07535, AA07728)
- Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498)
- The Netherlands Organization for Scientific Research (904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717)
- Biobanking and Biomolecular Resources Research Infrastructure (184.021.007)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- major depressive disorder, DNA methylation, epigenetics, monozygotic twin discordance, prefrontal cortex, sperm DNA methylation, leukocytes, machine learning, disease severity classification, age effects
- MeSH terms
- Adolescent, Adult, Aged, Depressive Disorder, Major, Major Depressive Disorder, Female, Humans, Leukocytes, Male, Middle Aged, Spermatozoa, Twins, Monozygotic, Prefrontal Cortex, CpG Islands, Epigenesis, Genetic, Microarray Analysis, Young Adult
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