Association of genes involved in calcium and potassium pathways with opioid dependence.

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. In addition to environmental influences, many studies have demonstrated the familial transmission of substance abuse, with heritability estimates ranging from 30%–80% (2). More recently, genome-wide association studies have been used to identify genetic risk factors for complex diseases including substance dependence. The most successful and replicable GWAS associations for substance dependence have been with variants in the gene cluster encoding the α5, α3, and β4 nicotinic receptor subunits on chromosome 15 that are associated with risk of nicotine dependence and other smoking-related traits (3–5). The GWAS on alcohol dependence and related traits have not yet provided conclusive evidence for the role of specific genetic factors, most likely because these studies have been underpowered compared with the nicotine dependence studies, the largest of which have used cigarettes per day as a proxy for nicotine dependence enabling sample sizes in the tens of thousands. Genome-wide significant results have been observed for alcohol dependence with low frequency variants within the alcohol dehydrogenase genes, but these variants are not well tagged by variants on GWAS chips (5,6). There are even fewer GWAS on illicit drug dependence, and similar to the alcohol dependence studies, the sample sizes for these studies are smaller than most of the GWAS for other psychiatric traits that have resulted in multiple genome-wide significant loci (http:// www.med.unc.edu/pgc/results#Results2Date). Gelernter et al. (7) used imputed minor allele dosage as the dependent variable and DSM-IV cocaine dependence symptom count in an association analysis and identified an intronic variant within the FAM53B gene that exhibited genome-wide significant association. In their article in this issue of Biological Psychiatry, Gelernter et al. (8) use the same analytic approach to identify genome-wide significant associations with opioid dependence. It is well recognized that the genetic etiology of complex psychiatric disorders such as substance dependence is most likely influenced by a mixture of many common variants with small effect and by rare variants with large effect. A major challenge in detecting these genetic risk factors is the statistical power needed to detect these variants of small effect. The discovery sample