# Functional convergence following disruption of diverse genes associated with cannabis use and major depression

> **NIH NIH DP1** · YALE UNIVERSITY · 2024 · $441,000

## Abstract

Project Summary
There is strong association between cannabis use and depression and suicide, but the underlying cellular links
are poorly understood. This presents a challenge for understanding how drug use can lead to additional
psychiatric disorders. It is believed that cannabis use alters the development of key brain regions which in turn
makes the brain more susceptible to additional stressors that could lead to major depressive disorder (MDD).
These findings are particularly concerning given the popularity of cannabis legalization. One of the key unsolved
problems is how to link drug use with specific molecular changes in the brain that can lead to depression. In this
proposal, we take the first steps to bridging this gap. First, we will use innovative single cell type postmortem
genomics to identify the molecular (transcriptomic and chromatin) changes occurring in the cannabis use
disorder (CUD) brain. We will focus our studies on two discreet brain regions: the dorsolateral prefrontal cortex
and the ventral striatum in 120 donors with CUD, MDD, and neurotypical controls. We will use reverse genetic
approaches to identify genomic alterations in the CUD brain that harbor GWAS risk signals for MDD. We
hypothesize that these alterations lead to widespread epigenomic changes that make the brain vulnerable to
stress and developing MDD. We will prioritize a credible set of genomic regions and genes and validate their
function in a human iPSC brain organoid model using massively parallel reporting assays (MPRA). We will also
test the effect THC (the active compound in cannabis) has on these organoids by comparing THC-exposed
organoids from donors with a history of CUD (but not MDD) with our MDD postmortem brain genomics to identify
convergent molecular mechanism changes. These studies will uncover genes driving MDD pathogenesis and
establish if cannabis use shares and drives these mechanisms. We expect this project will open new lines of
exploration in the comorbidity of substance use disorders and major depression and contribute broadly to
understanding the relationship between gene regulation and functional roles in cannabis use, which may identify
new therapeutic targets.

## Key facts

- **NIH application ID:** 10932680
- **Project number:** 1DP1DA060811-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Matthew J Girgenti
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $441,000
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932680

## Citation

> US National Institutes of Health, RePORTER application 10932680, Functional convergence following disruption of diverse genes associated with cannabis use and major depression (1DP1DA060811-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10932680. Licensed CC0.

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