# (Epi)genetic Risk Architectures in Opioid Dependent Brain

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $745,878

## Abstract

PROJECT SUMMARY/ABSTRACT
With nearly 20,000 overdose deaths in 2014 alone, opioid addiction (OA) has emerged as one
of the most pressing public health crises in recent US history. One-fifth of individuals who try
heroin develop an addiction to opioids. Genetics is a major contributor to OA with an estimated
60% heritability: only somewhat less than schizophrenia (80%) which has recently seen
substantial gains in identified underlying genetics. Yet, studies to date have failed to uncover
most of the genes that predispose individuals to OA, leaving the overwhelming fraction of OA
heritability unexplained. The proposed study takes a novel, integrated ‘omics-based strategy to
investigate the molecular basis of OA and uncover both genetic and epigenetic factors
associated with opioid addiction. The premise for our approach is founded on studies from our
labs and others implicating regulatory variation in common traits and diseases, including those
associated with complex brain phenotypes like addiction. We have collected the largest known
cohort of postmortem brains from addicts who overdosed on opioids, along with matched control
brains from non-users. From both cases and control specimens, we will isolate cells from 2
regions of the brain closely implicated in the addiction phenotype: the Prefrontal Cortex (PFC)
and the Nucleus Accumbens (NAc). In Aim 1, we propose ChIP-seq studies to identify
regulatory elements that distinguish cases from controls and define the opioid addiction
phenotype. The regulatory differences will be connected to their gene targets through high
resolution in situ Hi-C. In Aim 2, we propose QTL-based approaches to identify genetic variants
that underlie the regulatory differences (hmQTLs). We also propose eQTL analyses to identify
genetic variants that underlie differences in transcript levels between cases and controls. Aim 3
leverages the largest heroin addiction GWAS meta-analysis to date to test the hypothesis that
SNPs associated the chromatin and expression differences between cases and controls define
novel loci for predisposition to OA. Each Aim has the potential for discovery independent of the
others (differential HM, RNAexp, QTLs, and variant-phenotype associations) but their synergy is
the most powerful component of the proposed study: identifying regulatory pathways that
generate, not only phenotype associations, but hypothesized mechanisms for those
associations which can be the focus of new opioid addiction prevention and treatment
development.

## Key facts

- **NIH application ID:** 10167661
- **Project number:** 5R01DA043980-05
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Schahram Akbarian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $745,878
- **Award type:** 5
- **Project period:** 2017-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167661

## Citation

> US National Institutes of Health, RePORTER application 10167661, (Epi)genetic Risk Architectures in Opioid Dependent Brain (5R01DA043980-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10167661. Licensed CC0.

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