Archival Report| Volume 76, ISSUE 1, P66-74, July 01, 2014

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Genome-Wide Association Study of Opioid Dependence: Multiple Associations Mapped to Calcium and Potassium Pathways


      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.


      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.


      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.


      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.

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      Linked Article

      • Association of Genes Involved in Calcium and Potassium Pathways with Opioid Dependence
        Biological PsychiatryVol. 76Issue 1
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          Opioids 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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