# Investigating the Systems Genetics of the Patterns of Polysubstance Abuse and Addiction

> **NIH NIH R21** · YALE UNIVERSITY · 2020 · $177,109

## Abstract

Abstract. Polysubstance Substance Use (PSU) is common among individuals meeting
diagnosis for any substance use disorder (SUD) and is defined as the use of two or more
addictive drugs. These drug combinations are associated with increased short- and long-term
mental and physical health concerns. Due to the high degree of variability in PSU patterns,
limited data are available regarding the molecular mechanisms underlying PSU vulnerability.
The overall goal of this project is to use novel approaches based on genome-wide data to
dissect the fundamental biology of polysubstance abuse and addiction. In the R21 phase of this
proposal, we will conduct heritability and high-resolution cross-phenotype polygenic risk score
(PRS) analyses of probabilities of PSU classes in three moderately-large study populations
characterized by a high degree of PSU, our Yale-Penn cohort, the SAGE (Study of Addiction:
Genetics and Environment) cohort, and the ICGHD (International Consortium on the Genetics of
Heroin Dependence) cohort. The PSU pattern will be identified applying latent class analysis
(LCA) and a multinomial logistic regression procedure to substance use data available from the
SSADDA (Semi-structured Assessment for Drug Dependence and Alcoholism; Yale-Penn
Cohort), the SSAGA (Semi-Structured Assessment for the Genetics of Alcoholism; SAGE
cohort), and the SSAGA-OZ (SSAGA – Australia; ICGHD cohort). We expect that the R21-Phase analyses will identify heritable PSU patterns and gene sets associated with them,
providing the background necessary to investigate PSU in other molecular paradigms. In the
R33 phase of the project, we will test the R21-phase results with respect to two different
settings: 1) longitudinal PSU data; and 2) PSU-induced epigenetic changes. Re-contacting a
sub-sample of the Yale-Penn cohort, we will be able to assess the trajectory of PSU patterns
and the consequences of PSU and to test whether the genetic factors associated with the initial
PSU status predict the PSU trajectories and consequences. Similarly, we will also test whether
heritable PSU correlates with epigenetic changes and whether these mediate health outcomes.
The expected results of the R33 phase will provide multiple findings related to the biology of
PSU that can improve clinical practice, deliver new therapeutic targets, and open new directions
in molecular investigations of PSU.

## Key facts

- **NIH application ID:** 9867716
- **Project number:** 5R21DA047527-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** RENATO POLIMANTI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $177,109
- **Award type:** 5
- **Project period:** 2019-02-15 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867716

## Citation

> US National Institutes of Health, RePORTER application 9867716, Investigating the Systems Genetics of the Patterns of Polysubstance Abuse and Addiction (5R21DA047527-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9867716. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*