# Genetic Vulnerability for Sustained Multi-Substance Use in MVP

> **NIH VA I01** · VA CONNECTICUT HEALTHCARE SYSTEM · 2020 · —

## Abstract

Harmful substance use (alcohol, tobacco, and/or prescription opioids) is common and twin studies suggest a
substantial genetic role. Further, combined use of alcohol with tobacco and tobacco with opioids, commonly
occurs suggesting that environmental and genetic risks for these behaviors overlap. However, identified
genetic variation explains only a small proportion of the phenotypic variation for individual or combined
substance use. Studies aiming to identify shared genetic pathways across substances (pleiotropy) have
yielded inconsistent results. Among the major challenges to gene finding for these traits are phenotypic
ambiguity, measurement bias, and inadequate statistical power to detect the small genetic effects associated
with complex disorders. Individual clinical assessments often do not capture all substances of interest or
relevant clinical factors (e.g., chronic pain) and are subject to substantial variation and bias depending upon
the patient's health state, the clinical setting in which the assessment occurs, and the clinician making the
assessment. Administrative International Classification of Diseases (ICD) codes derived from these
assessments are frequently used because they are readily available for large numbers of subjects, but they
can add another layer of inaccuracy and bias. The unique, rich, longitudinal clinical data available within the
Veterans Healthcare Administration (VA) combined with data available from the Million Veteran Program
(MVP) is enabling us to overcome these limitations. We began with widely available and repeated electronic
health record (EHR)-based metrics: AUDIT-C for hazardous alcohol; current/past/never smoking status for
tobacco; and morphine equivalent daily dose (MEDD) from pharmacy fill/refill records for prescription opioids.
Longitudinal summary metrics derived from these measures were initially validated in the Veterans Aging
Cohort Study (VACS) and then extended to MVP, validating them against additional criterion standards and in
a much larger, more generalizable, sample. Importantly, MVP also allowed us to validate against genetic
criterion standards, previously identified single nucleotide polymorphisms (SNPs). This yielded Electronic
Health Record (EHR)-based, CritErion-validated Longitudinal (ExCEL) phenotypes that were substantially
more strongly associated with criterion and content standards for alcohol (1, 2), tobacco (3), and prescription
opioids [Becker, in preparation] than alternative phenotypes. Genome-wide association studies (GWASs) of
alcohol, tobacco, and opioids using ExCEL phenotypes are underway and have both reproduced prior findings
and yielded many novel associations of SNPs and genes with these conditions. We have shared ExCEL
phenotypes with Alpha and Beta project groups via the MVP wiki and the MVP Phenotype Workgroup. We are
currently conducting joint GWASs of ExCEL phenotypes for tobacco and alcohol (Zhao and Dao) and will soon
initiate joint GWASs of ExCEL phe...

## Key facts

- **NIH application ID:** 9780702
- **Project number:** 1I01BX004820-01A1
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** Amy Caroline Justice
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9780702

## Citation

> US National Institutes of Health, RePORTER application 9780702, Genetic Vulnerability for Sustained Multi-Substance Use in MVP (1I01BX004820-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9780702. Licensed CC0.

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