# Identifying Genetic Variants Associated with Opioid Overdose Mortality

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $917,989

## Abstract

The CDC has documented the worsening “opioid overdose epidemic” in the U.S. Opioid overdose
deaths have increased among males and females, non-Hispanic whites and blacks, and all age
groups over age 25.24 Interrelated trends contributing to the epidemic include an increase in
prescription opioid overdose deaths spanning more than 15 years and more recent surges in
overdose deaths due to illicit opioids (i.e., heroin and fentanyl-related drugs). Overdose deaths
involving heroin rose nearly five-fold in the U.S. from 2010 to 2016 while those involving
fentanyl and its analogues more than doubled from 2015 to 2016.24,26 Research to improve
understanding of the pathophysiology of opioid-induced respiratory depression is thus a public health
imperative. Prior genetic research in this area has been limited to candidate gene studies that genotyped a
handful of SNPs in samples of very modest size that consisted primarily of European ancestry (EA) individuals.
We are proposing to conduct the first GWAS of death due to opioid-induced respiratory depression. Our large
EA and African American (AA) sub-samples will each exceed that of the largest prior study by well over an
order of magnitude. We will utilize two distinct comparison groups, large previously-genotyped EA and AA
samples of opioid dependent individuals and general population members that are well-suited, respectively, to
identify effects contingent upon repeated use and those shared with liability of opioid use disorder. Our study
design focuses on a definitive outcome measure, death due to opioid-induced respiratory depression, which
is expected to provide additional power for our investigation. Many prior studies have examined less clearly
demarcated outcomes (clinically observed respiratory depression) in convenience samples (e.g. pediatric
surgical patients). This revised proposal is very well-powered to identify common genetic variants in EAs and
AAs associated with liability for opioid-induced respiratory depression. We are also proposing to conduct the
first examination performed in human opioid overdose decedents of gene expression changes in brain
regions involved in opioid-induced respiratory depression including the preBötzinger complex,
parabrachial/Kölliker-Fuse nuclei (PB/KF), and raphe nucleus. This complementary investigation will provide
additional insight into the pathophysiology underlying this process and enable examination of alterations in
gene expression associated with common variants implicated in the GWAS. The specific aims are: 1) To
obtain DNA from 15,000 accidental opioid overdose decedents (N's EA ~10,000; AA ~5000). 2) To conduct a
GWAS of opioid-induced respiratory depression including risk shared across opioids, and drug-specific effects,
comparing these individuals to two large previously GWAS-genotyped groups of AA and EA individuals: 1)
those with opioid use disorder; and 2) those ascertained in general population samples. 3) To examine
differential gene expre...

## Key facts

- **NIH application ID:** 9901498
- **Project number:** 5R01DA046436-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** ARPANA AGRAWAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $917,989
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901498

## Citation

> US National Institutes of Health, RePORTER application 9901498, Identifying Genetic Variants Associated with Opioid Overdose Mortality (5R01DA046436-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9901498. Licensed CC0.

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