Major depressive disorder (MDD) is a devastating psychiatric disorder that affects millions of Americans. Despite substantial research, no specific risk factor has yet been identified as having a causal role in MDD. Epigenetic modifications, especially DNA methylation, are increasingly being recognized as a key mechanism involved in the pathogenesis of depression. However, the biological pathways linking aberrant methylation to depression remain poorly understood. This uncertainty greatly hampers our ability to implement early diagnosis, prevention and treatment for this debilitating disorder. The objective of this study is to identify functional epigenetic determinants for MDD. Our central hypothesis is that aberrant DNA methylation and resulting alterations in gene expression are associated with MDD. The rationale for the proposed research is that: once we know the epigenetic determinants for depression, we will be able to develop novel epigenetic markers and therapeutic targets for risk assessment, prevention and treatment of MDD and related psychiatric conditions. We proposed three specific aims: (1) Identify differentially methylated regions (DMRs) associated with MDD.
This aim i s to conduct an epigenome-wide DNA methylation analysis to identify epigenetic variations contributing to MDD in monocytes DNA from 100 monozygotic (MZ) discordant twin pairs from the University of Washington Twin Registry (UWTR), a large community-based twin registry in the U.S. (2) Replicate the top 50 ranked genes from Aim 1 in two independent samples, including 80 MZ discordant twin pairs recruited from the same registry and 36 postmortem brain tissue of well-characterized MDD patients and matched controls. (3) Determine the functional importance of the positive methylation findings in both blood and brain by profiling gene expression levels in each of the four brain regions (frontal cortex, hippocampus, amygdala, and cingulate cortex). Differential expressed genes related to MDD will be identified. Integrative analyses will be performed to elucidate the connections between DNA methylation patterns and gene expression of cognate genes in relation to MDD. The proposed study is the only one of its kind to identify functional epigenetic determinants for MDD in a well- matched MZ discordant twin sample, followed by replication in postmortem brain tissue, the affected organ in MDD. The work proposed here is expected to have an important positive impact, because genes with both differential methylation and expression are highly likely to provide novel epigenetic targets for prevention, intervention and treatment for depression and its related psychiatric conditions in addition to fundamentally advancing the fields of psychiatric genetics.

Public Health Relevance

Epigenetic factors play an important role in major depression. However, specific genes and epigenetic pathways involved in major depression remain largely unknown. This study aims to discover functional epigenetic determinants for major depression using a monozygotic discordant twin design, followed by replication in postmortem brain tissue, with the belief that such knowledge is likely to provide novel epigentic targets for early diagnosis, prevention, intervention and treatment of this debilitating disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH097018-02
Application #
8715864
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Senthil, Geetha
Project Start
2013-08-15
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$610,801
Indirect Cost
$89,125
Name
Tulane University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Peng, Hao; Zhu, Yun; Strachan, Eric et al. (2018) Childhood Trauma, DNA Methylation of Stress-Related Genes, and Depression: Findings From Two Monozygotic Twin Studies. Psychosom Med 80:599-608
Peter, Cyril J; Fischer, Laura K; Kundakovic, Marija et al. (2016) DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition. Biol Psychiatry 80:765-774
Gymrek, Melissa; Willems, Thomas; Guilmatre, Audrey et al. (2016) Abundant contribution of short tandem repeats to gene expression variation in humans. Nat Genet 48:22-9
Joshi, Ricky S; Garg, Paras; Zaitlen, Noah et al. (2016) DNA Methylation Profiling of Uniparental Disomy Subjects Provides a Map of Parental Epigenetic Bias in the Human Genome. Am J Hum Genet 99:555-566
Quilez, Javier; Guilmatre, Audrey; Garg, Paras et al. (2016) Polymorphic tandem repeats within gene promoters act as modifiers of gene expression and DNA methylation in humans. Nucleic Acids Res 44:3750-62
Watson, Corey T; Roussos, Panos; Garg, Paras et al. (2016) Genome-wide DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer's disease. Genome Med 8:5
Bilgin Sonay, Tugce; Carvalho, Tiago; Robinson, Mark D et al. (2015) Tandem repeat variation in human and great ape populations and its impact on gene expression divergence. Genome Res 25:1591-9
Hernando-Herraez, Irene; Garcia-Perez, Raquel; Sharp, Andrew J et al. (2015) DNA Methylation: Insights into Human Evolution. PLoS Genet 11:e1005661
Kappil, Maya A; Green, Benjamin B; Armstrong, David A et al. (2015) Placental expression profile of imprinted genes impacts birth weight. Epigenetics 10:842-9
Zhao, Jinying; An, Qiang; Goldberg, Jack et al. (2015) Promoter methylation of glucocorticoid receptor gene is associated with subclinical atherosclerosis: A monozygotic twin study. Atherosclerosis 242:71-6

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