Document text
Principal Investigator: ARPANA AGRAWAL
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2019
Award: $661,450
Funding agency: National Institute on Drug Abuse
A recent CDC report observed that heroin use has increased in men and women across the U.S., including
most age groups and all income levels. The current heroin epidemic follows an ongoing prescription opioid
misuse epidemic that has helped drive the spike in heroin use. Research to improve understanding of the
pathophysiology of opioid use disorder (OUD) is thus a public health imperative. OUD is a moderately heritable
(40-60%) disorder; however, few replicated genetic findings have been identified. One reason for this is that a
definitive control sample for association studies of OUD has not been established. Building on candidate gene
data findings from the Comorbidity and Trauma Study (CATS) that noted association results for OUD vary
substantially with substance exposure in the comparison group, and consistent with well-replicated findings
from comparisons of non-dependent, regular smokers to nicotine dependent individuals, we conducted a
genome-wide association study (GWAS) in CATS limiting controls to opioid misusers. The strongest
association signal observed was for cornichon family AMPA receptor auxiliary protein 3 (CNIH3) SNPs.
Replication performed in two additional GWAS samples yielded a genome-wide significant (GWS) meta-
analytic p value of 4.3 E-9 for rs10799590, the most strongly associated SNP. These findings, coupled with
exciting results from a pilot meta-analysis included in this revised application demonstrate the utility of
comparisons to samples of non-OUD opioid misusers (even those with modest N's) to identify novel
loci that would not be detected in comparisons to general population controls. The current application
proposes to ascertain, assess, and genotype groups [African American (AA) N=1000 and European American
(EA) N=1000] of individuals with a limited history of opioid misuse who have never met criteria for an opioid
use disorder (i.e., non-OUD misusers as controls). Individuals with OUD (N=400 AA and N=400 EA) will also
be assessed, and genotyped and combined with OUD cases from other sources for a GWAS. The specific
aims are: Aim 1) To ascertain, comprehensively assess, and obtain DNA from 1000 AA and 1000 EA
individuals with a history of limited opioid misuse who have never met criteria for opioid use disorder (OUD)
and smaller numbers of individuals with OUD (400 AA and 400 EA) OUD - the first effort targeting large-scale
collection of non-OUD opioid misusers to serve as controls. Aim 2) To conduct mega-analyses: 1) comparing
the current proposal's AA and EA non-OUD opioid misusers to expanded groups of OUD cases that also
include previously GWAS-genotyped samples, AA (N=2093) and EA (N=6154); 2) with further expanded
samples of both cases and controls (AA totals: 4366 OUD cases; 1699 non-OUD misuser controls; EA
totals: 10,106 OUD cases; 2138 non-OUD misuser controls) from other sources. Aim 3) To examine
whether subjective responses to initial opioid use and stages of use mediate or moderate the relationship
between top SNPs from the mega-analysis and progression to OUD.
Terms: <AMPA Receptors><Admission><Admission activity><Affect><African American><Afro American><Afroamerican><American><Area><Black Populations><CDC><Candidate Disease Gene><Candidate Gene><Cell Communication and Signaling><Cell Signaling><Centers for Disease Control><Centers for Disease Control and Prevention><Centers for Disease Control and Prevention (U.S.)><Chills><Clinical Trial Overviews><Collection><Comorbidity><Coupled><DNA><Data><Data Pooling><Deoxyribonucleic Acid><Development><Diacetylmorphine><Diamorphine><Disease><Disorder><Dose><Drug Exposure><Drugs><Dysfunction><Economic Income><Economical Income><Epidemic><European><Exposure to><Family><Family Study><Functional disorder><GWA study><GWAS><General Population><General Public><Genes><Genetic><Genetic study><Genotype><Glutamates><Heritability><Heroin><History><Income><Individual><Intracellular Communication and Signaling><L-Glutamate><Letters><Low Prevalence><Maps><Mediating><Medication><Meta-Analysis><Missouri><Nicotine Dependence><Nonnarcotic Analgesics><Nonopioid Analgesics><Opiate Addiction><Opiate Dependence><Opiates><Opioid><Opioid Analgesics><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Physiopathology><Population Control><Prescription Drug Monitoring Program><Prevalence><Proteins><Public Health><Recording of previous events><Reporting><Research><Risk><Sampling><Sampling Studies><Signal Transduction><Signal Transduction Systems><Signaling><Smoker><Source><Suggestion><Trauma><Twin Studies><Uncertainty><United States Centers for Disease Control><United States Centers for Disease Control and Prevention><Variant><Variation><Woman><addiction><addictive disorder><age group><base><biological signal transduction><black American><case control><co-morbidity><cohort><comparison group><cost effective><database of Genotypes and Phenotypes><dbGaP><developmental><diamorphine overdose><doubt><drug/agent><genetic association><genome scale><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genome-wide><genomewide><genomewide association scan><genomewide association studies><genomewide association study><glutamatergic><heroin intake><heroin overdose><heroin use><illicit opiate><illicit opioid><improved><intravenous opiate><intravenous opioid><licit opioid><men><men's><nicotine addiction><nicotine dependent><non-medical opioid use><non-medical use of prescription opiates><non-medical use of prescription opioids><non-narcotic analgesic><non-opiate analgesic><non-opioid><non-opioid analgesic><nonmedical opioid use><nonmedical use of prescription opiates><nonmedical use of prescription opioids><nonopiate analgesic><nonopioid><novel><opiate analgesia><opiate analgesic><opiate consumption><opiate deaths><opiate drug use><opiate injection><opiate intake><opiate medication><opiate misuse><opiate mortality><opiate overdose><opiate pain medication><opiate pain reliever><opiate related overdose><opiate use><opiate use disorder><opioid addiction><opioid analgesia><opioid analgesic misuse><opioid anesthetic><opioid consumption><opioid deaths><opioid dependence><opioid dependent><opioid drug overdose><opioid drug use><opioid induced overdose><opioid injection><opioid injector><opioid intake><opioid intoxication><opioid medication><opioid medication misuse><opioid medication overdose><opioid misuse><opioid mortality><opioid overdose><opioid overdose death><opioid pain medication><opioid pain reliever><opioid painkiller><opioid poisoning><opioid prescription medication misuse><opioid related death><opioid related overdose><opioid toxicity><opioid use><opioid use disorder><overdose death><pathophysiology><prescribed opiate><prescribed opioid><prescription monitoring program><prescription opiate><prescription opiate misuse><prescription opioid><prescription opioid misuse><protective effect><response><success><trend><whole genome association analysis><whole genome association studies><whole genome association study>