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.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Biological Psychiatry
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- The Economic Costs of Drug Abuse in the United States, 1992–2002.Executive Office of the President, Washington, DC2004 (Publication No. 207303)
- The genetics of addictions: Uncovering the genes.Nat Rev Genet. 2005; 6: 521-532
- A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.Nature. 2008; 452: 638-642
- Genomewide association study of cocaine dependence and related traits: FAM53B identified as a risk gene [published online ahead of print August 20].Mol Psychiatry. 2013; (doi:10.1038/mp.2013.99)
- The collaborative study on the genetics of alcoholism: An update.Alcohol Res Health. 2002; 26: 214-218
- Drug use and dependence in cocaine dependent subjects, community-based individuals, and their siblings.Drug Alcohol Depend. 2008; 95: 14-22
- Genomewide linkage scan for opioid dependence and related traits.Am J Hum Genet. 2006; 78: 759-769
- Genomewide linkage scan for cocaine dependence and related traits: Linkages for a cocaine-related trait and cocaine-induced paranoia.Am J Med Genet Neuropsych Genet. 2005; 136: 45-52
- Diagnostic Reliability of the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA).Drug Alcohol Depend. 2005; 80: 303-312
- Diagnostic and Statistical Manual of Mental Disorders.4th ed. American Psychiatric Press, Washington, DC1994
- Detection of specific polymerase chain reaction product by utilizing the 5’→3’ exonuclease activity of Thermus aquaticus DNA polymerase.Proc Natl Acad Sci U S A. 1991; 88: 7276-7280
- PLINK: A toolset for whole-genome association and population-based linkage analysis.Am J Hum Genet. 2007; 81: 559-575
- Principal components analysis corrects for stratification in genome-wide association studies.Nat Genet. 2006; 38: 904-909
- Population structure and eigenanalysis.PLoS Genet. 2006; 2: e190
- Novel genes identified in a high-density genome wide association study for nicotine dependence.Hum Mol Genet. 2007; 16: 24-35
- A flexible and accurate genotype imputation method for the next generation of genome-wide association studies.PLoS Genet. 2009; 5: e1000529
- A map of human genome variation from population-scale sequencing.Nature. 2010; 467: 1061-1073
- Longitudinal data analysis for discrete and continuous outcomes.Biometrics. 1986; 42: 121-130
- METAL: Fast and efficient meta-analysis of genomewide association scans.Bioinformatics. 2010; 26: 2190-2191
- Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix.Heredity (Edinb). 2005; 95: 221-227
- Fine mapping of calcineurin (PPP3CA) gene reveals novel alternative splicing patterns, association of 5’UTR trinucleotide repeat with addiction vulnerability, and differential isoform expression in Alzheimer’s disease.Subst Use Misuse. 2010; 45: 1809-1826
- Whole-genome association study of bipolar disorder.Mol Psychiatry. 2008; 13: 558-569
- CACNA1C (rs1006737) is associated with schizophrenia.Mol Psychiatry. 2010; 15: 119-121
- Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis.Lancet. 2013; 381: 1371-1379
- Local potassium signaling couples neuronal activity to vasodilation in the brain.Nat Neurosci. 2006; 9: 1397-1403
- Opiate activation of potassium conductance inhibits calcium action potentials in rat locus coeruleusneurones.Br J Pharmacol. 1983; 80: 225-228
- Characterization of a central Ca2+/calmodulin-dependent protein kinase IIalpha/beta binding domain in densin that selectively modulates glutamate receptor subunit phosphorylation.J Biol Chem. 2010; 286: 24806-24818
- Drug wanting: Behavioral sensitization and relapse to drug-seeking behavior.Pharmacol Rev. 2011; 63: A-R
- Hippocampal GluA1-containing AMPA receptors mediate context-dependent sensitization to morphine.J Neurosci. 2011; 31: 16279-16291
- Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease.Hum Mutat. 2005; 25: 270-277
- Association of amyloid precursor protein-binding protein, family B, member 1 with nicotine dependence in African and European American smokers.Hum Genet. 2008; 124: 393-398
- Association within a family of a balanced autosomal translocation with major mental illness.Lancet. 1990; 336: 13-16
- 708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: Analysis for association with psychiatric disorder and cognitive traits [published online ahead of print June 4].Mol Psychiatry. 2013; (doi:10.1038/mp.2013.68)
- A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition.Proc Natl Acad Sci U S A. 2008; 105: 7076-7081
- Deep resequencing of 17 glutamate system genes identifies rare variants in DISC1 and GRIN2B affecting risk of opioid dependence [published online ahead of print July 16]. 2013; (doi:10.1111/adb.12072)Addict Biol. 2013; (doi:10.1111/adb.12072)
- Linkage analysis followed by association show NRG1 associated with cannabis dependence in African-Americans.Biol Psychiatry. 2012; 72: 637-644
- Effects of differential genotyping error rate on the type I error probability of case-control studies.Hum Hered. 2006; 61: 55-64
- The effect of minor allele frequency on the likelihood of obtaining false positives.BMC Proc. 2009; 3: S41
Published online: October 21, 2013
Accepted: August 27, 2013
Received in revised form: July 29, 2013
Received: May 31, 2013
© 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
ScienceDirectAccess this article on ScienceDirect
- 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.