# Interpreting the regulatory mechanisms underlying the predisposition to substance use disorders

> **NIH NIH DP1** · CARNEGIE-MELLON UNIVERSITY · 2020 · $474,300

## Abstract

Summary/Abstract
 Substance use disorders have a profound impact on human health and wellbeing. The development of
new treatments for these disorders has remained difficult due to the complexity of the neural circuits and the
underlying genetic mechanisms. Recent genome-wide association studies have begun to identify a few of loci
associated with the predisposition to addiction, with many more loci are implicated with lower confidence. The
majority of the genetic variants associated with complex brain disorders, including substance use, are likely to
be located in non-coding regulatory regions, particularly enhancers, and not within protein-coding genes.
Despite the importance of enhancer regions in the brain, the computational and experimental tools to study
their function are still in their infancy.
 To work towards deciphering this critical biological mechanism underlying substance use disorders, we
seek to build a framework to study the function of both human and mouse brain enhancer regions in vivo. First,
we will analyze publically available genetic and epigenetic data sets to identify human genetic variation at
enhancers regions that is likely to influence substance use predisposition. Next, we will measure the impact of
that genetic variation using a high-throughput reporter assay, which has the ability to simultaneously test the
activity of thousands of enhancers across the mouse brain in vivo under different conditions. Finally, we will
validate those predictions using CRISPR interference on conserved orthologous enhancers in the mouse. In an
initial test case, we will apply our methods to interpret a genome-wide association study of smoking behavior
using cell type-specific human epigenomics. The key candidates that result from the computational analysis
will be screened and validated in a mouse model of nicotine exposure.
 The result of our research effort will be a map that links high-confidence and low-confidence substance
use-associated genetic variation to neural enhancer function. Furthermore, the flexible computational and
experimental framework has the potential to study any combination of candidate enhancers and genetic
variants in the context of different brain regions, different cell types, and different animal models.

## Key facts

- **NIH application ID:** 9960515
- **Project number:** 5DP1DA046585-03
- **Recipient organization:** CARNEGIE-MELLON UNIVERSITY
- **Principal Investigator:** Andreas Robert Pfenning
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $474,300
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960515

## Citation

> US National Institutes of Health, RePORTER application 9960515, Interpreting the regulatory mechanisms underlying the predisposition to substance use disorders (5DP1DA046585-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9960515. Licensed CC0.

---

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