# Genetic architecture of substance use disorders and major depression

> **NIH VA IK2** · PHILADELPHIA VA MEDICAL CENTER · 2024 · —

## Abstract

Major depressive disorder (MDD) occurs commonly among individuals both with alcohol use disorder
(AUD) and prescription opioid use disorder (POUD) and such comorbidity is highly prevalent in Veterans.
Given the poor outcomes (e.g., relapse, treatment drop out, impaired functioning) and increased mortality of
individuals with these comorbid disorders, a better understanding of their etiology and the basis for the
comorbidity is of great clinical importance. Although common pathways for the development of these
comorbidities have been proposed (e.g., self-medication), the shared genetic pathways of MDD and these
substance use disorders (SUDs) have not been well characterized, an effort that is complicated by phenotypic
heterogeneity. For example, not all individuals present with the same rate of substance use or severity of SUD
symptoms. Consistent with the phenotypic complexity, these SUDs are likely to be genetically heterogeneous,
with multiple genetic pathways leading to AUD or POUD. Thus, by refining the SUD phenotype and reducing
the phenotypic heterogeneity, studying a large number of well-defined cases and controls, we may reduce the
genetic heterogeneity and identify true genetic associations. Moreover, the Million Veteran Program (MVP)
sample makes possible the investigation of causal pathways. The objectives of this CDA-2 proposal are to
characterize the genetic architecture of AUD and POUD, with and without MDD, identify novel relationships
between genetic liability for the disorders and other phenotypes (i.e., pleiotropy), and specify causal pathways
using the MVP sample. The specific aims are to: (1) identify Veterans with AUD, POUD, and co-occurring MDD
and characterize their depressive symptomatology and substance use using ICD-9/10 diagnoses and self-
report measures; (2) assess the genetic architecture and causal relations of AUD and AUD with co-occurring
MDD; and (3) the genetic architecture and causal relations of POUD and POUD with co-occurring MDD.
 Using all available data, Veterans with AUD will be identified in VINCI and categorized based on the
presence co-occurring MDD. Similarly, Veterans treated chronically with prescription opioids who have been
diagnosed with an opioid use disorder will be identified and their MDD history ascertained. Data on key
medical and psychiatric comorbidities (e.g., pain, PTSD) will also be extracted. Control and comparison groups
of Veterans without comorbid AUD or POUD and MDD and with MDD alone will be ascertained. We will also
extract self-reported alcohol consumption data using the Alcohol Use Disorders Identification Test-
Consumption and self-reported depressive symptoms using the Patient Health Questionnaire-2, both
administered regularly in primary care. Three separate genome-wide association studies of individuals with an
SUD (first AUD, secondly POUD) with MDD, an SUD without MDD, and MDD (no SUD) will be conducted on
the GenISIS platform using PLINK. Using summary statistics from t...

## Key facts

- **NIH application ID:** 10930685
- **Project number:** 5IK2CX002336-03
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** Emily Hartwell
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930685

## Citation

> US National Institutes of Health, RePORTER application 10930685, Genetic architecture of substance use disorders and major depression (5IK2CX002336-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10930685. Licensed CC0.

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