# Integrative Genomics of the Corticolimbic Circuit in Major Depressive Disorder

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $830,273

## Abstract

Major Depressive Disorder (MDD) is a frequently recurring disorder that is the second leading cause of
disability worldwide and a significant risk factor for suicide. Despite better recognition and increased treatment,
the prevalence of MDD and the overall rates of suicide remain unchanged. Although a wide variety of
treatments are available, their overall efficacy remains modest, and only a third of treated patients show full
remission. Novel treatments are urgently needed, yet the development of new types of antidepressants has
been hindered by our limited understanding of the pathophysiology of MDD. In this proposal, we seek to
perform the largest and most comprehensive molecular study of MDD in post-mortem brains to date. We will
use the substantial post-mortem brain collection of the Lieber Institute for Brain Development to
comprehensively study genome-wide expression and epigenetic signatures that are associated with MDD and
suicide in the three brains regions of the corticolimbic circuit, consisting of the Anterior Cingulate Cortex (ACC),
the Amygdala, and the Dorsal Lateral Prefrontal Cortex (DLPFC). We propose to perform RNA sequencing,
DNA-methylation and chromatin accessibility (ATAC-seq) assays in the ACC and Amygdala of 400 post-
mortem brain samples and to combine these results with of the DLPFC from Brainseq project. Our aims will
then be to: (1) conduct case-control analyses of these two brain regions along with RNA-seq of the DLPFC to
identify molecular signatures associated with MDD and integrate our findings across molecular profiles to
provide additional mechanistic insights into the causes of MDD; (2) to take advantage of recent identification of
genome-wide significant findings from GWAS studies in MDD and its closely related trait, neuroticism, to fine-
map associated loci and identify expression quantitative trait loci (eQTLs) and changes in methylation and/or
chromatin that may mediate the association between genetic marker and expression; (3) to perform a case-
only analysis of the cases with MDD who died by suicide compared with cases with MDD who died by natural
causes to identify molecular signatures and mechanisms associated with suicide; and, finally (4) to perform a
replication of the main findings in an independent sample of 50 cases and 50 controls. In order to ensure the
success of this proposal, we have assembled a strong interdisciplinary investigative team from the Johns
Hopkins Mood Disorder research group and the Lieber Instituted for Brain development, with expertise in mood
disorders, genomics, post-mortem brain studies, and statistical genetics. By investigating the functional
genomics and epigenomics of MDD in a large and well characterized post-mortem brain collection, our study
has strong potential to identify genes and networks that could be novel targets for a new generation of
treatments.

## Key facts

- **NIH application ID:** 9935959
- **Project number:** 5R01MH111721-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Fernando Sampaio Goes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $830,273
- **Award type:** 5
- **Project period:** 2017-09-06 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935959

## Citation

> US National Institutes of Health, RePORTER application 9935959, Integrative Genomics of the Corticolimbic Circuit in Major Depressive Disorder (5R01MH111721-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9935959. Licensed CC0.

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