Background
We report a genome-wide association study (GWAS) of two populations, African-American
and European-American (AA, EA) for opioid dependence (OD) in three sets of subjects,
to identify pathways, genes, and alleles important in OD risk.
Methods
The design employed three phases (on the basis of separate sample collections). Phase
1 included our discovery GWAS dataset consisting of 5697 subjects (58% AA) diagnosed
with opioid and/or other substance dependence and control subjects. Subjects were
genotyped with the Illumina OmniQuad microarray, yielding 890,000 single nucleotide
polymorphisms (SNPs) suitable for analysis. Additional genotypes were imputed with
the 1000 Genomes reference panel. Top-ranked findings were further evaluated in Phase
2 by incorporating information from the publicly available Study of Addiction: Genetics
and Environment dataset, with GWAS data from 4063 subjects (32% AA). In Phase 3, the
most significant SNPs from Phase 2 were genotyped in 2549 independent subjects (32%
AA). Analyses were performed with case-control and ordinal trait designs.
Results
Most significant results emerged from the AA subgroup. Genome-wide-significant associations
(p < 5.0 × 10−8) were observed with SNPs from multiple loci–KCNG2*rs62103177 was most significant after combining results from datasets in every phase
of the study. The most compelling results were obtained with genes involved in potassium
signaling pathways (e.g., KCNC1 and KCNG2). Pathway analysis also implicated genes involved in calcium signaling and long-term
potentiation.
Conclusions
This is the first study to identify risk variants for OD with GWAS. Our results strongly
implicate risk pathways and provide insights into novel therapeutic and prevention
strategies and might biologically bridge OD and other non–substance dependence psychiatric
traits where similar pathways have been implicated.
Key Words
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Article info
Publication history
Published online: October 21, 2013
Accepted:
August 27,
2013
Received in revised form:
July 29,
2013
Received:
May 31,
2013
Identification
Copyright
© 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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- Association of Genes Involved in Calcium and Potassium Pathways with Opioid DependenceBiological PsychiatryVol. 76Issue 1
- PreviewOpioids such as morphine, oxycodone, and fentanyl are widely used as effective analgesics for treating acute and chronic pain. Although appropriate use of opioid analgesics is an essential part of effective pain management, abuse and dependence on opioids pose a threat to health and have a devastating social and economic impact on families, communities, and nations. In a systematic analysis of the epidemiology of drug dependence with “global burden of disease,” Degenhardt et al. (1) identified opioid dependsence as the largest contributor to the direct burden of disease among all illicit drugs.
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