This application is dedicated to understanding of primary molecular cause(s) of major depressive disorder (MDD). Unlike the majority of etiological studies that concentrate on genetic and/or environmental factors, the emphasis of this project is shifted to the inter-individual variation of epigenetic modifications of DMA. The epigenetic theory can provide a cohesive interpretation for numerous epidemiological, clinical, and molecular findings in MDD. Such include the non-Mendelian mode of inheritance of MDD, molecular effects of adverse life events, discordance of monozygotic twins, sex differences in susceptibility to the disease, major fluctuations in the disease course, and inconsistent findings of molecular genetic studies. In this project, two null hypotheses will be tested: i) there is no association between epigenetic changes and MDD, and ii) if such association exists, it is non-causal. Epigenetic profiles will be investigated in 850 DNA samples from: a) monozygotic twins discordant for MDD, b) unrelated MDD patients and matched controls (peripheral blood samples, post-mortem brain tissues, and sperm samples), and c) MD0D patients during remission vs. relapse. DNA methylation profiles will be identified through the microarray-based mapping of unmethylated and hypermethylated fractions of genomic DNA. Two types of microarrays will be used: i) 12,192- element CpG island microarray that interrogates gene promoter regions, and ii) 2,000-element microarray that investigates the genes of proteins that are of primary interest in MDD, such as serotonin transporter and glucocorticoid receptor. Bioinformatics tools will be used to process over 12 M microarray data points in order to identify disease specific DNA methylation changes in the affected individuals vs. controls in both within and between all the listed comparisons. If the null hypotheses cannot be rejected, the study will provide a new perspective on the fundamental issues in MDD and other complex diseases.
| Pal, Mrinal; Ebrahimi, Sasha; Oh, Gabriel et al. (2016) High Precision DNA Modification Analysis of HCG9 in Major Psychosis. Schizophr Bull 42:170-7 |
| Oh, Gabriel; Wang, Sun-Chong; Pal, Mrinal et al. (2015) DNA modification study of major depressive disorder: beyond locus-by-locus comparisons. Biol Psychiatry 77:246-255 |
| Kriukien?, Edita; Labrie, Viviane; Khare, Tarang et al. (2013) DNA unmethylome profiling by covalent capture of CpG sites. Nat Commun 4:2190 |
| Khare, Tarang; Pai, Shraddha; Koncevicius, Karolis et al. (2012) 5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary. Nat Struct Mol Biol 19:1037-43 |
| Kaminsky, Z; Tochigi, M; Jia, P et al. (2012) A multi-tissue analysis identifies HLA complex group 9 gene methylation differences in bipolar disorder. Mol Psychiatry 17:728-40 |
| Labrie, Viviane; Pai, Shraddha; Petronis, Arturas (2012) Epigenetics of major psychosis: progress, problems and perspectives. Trends Genet 28:427-35 |
| Vedadi, Masoud; Barsyte-Lovejoy, Dalia; Liu, Feng et al. (2011) A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol 7:566-74 |
| Ptak, Carolyn; Petronis, Arturas (2010) Epigenetic approaches to psychiatric disorders. Dialogues Clin Neurosci 12:25-35 |
| Petronis, Arturas (2010) Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature 465:721-7 |
| Kaminsky, Zachary A; Tang, Thomas; Wang, Sun-Chong et al. (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41:240-5 |
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