Abstract
Substance dependence is a complex environmental and genetic disorder with significant social and medical concerns. Understanding the etiology of substance dependence is imperative to the development of effective treatment and prevention strategies. To this end, substantial effort has been made to identify genes underlying substance dependence, and in recent years, genome-wide association studies (GWASs) have led to discoveries of numerous genetic variants for complex diseases including substance dependence. Most of the GWAS discoveries were only based on single nucleotide polymorphisms (SNPs) and a single dichotomized outcome. By employing both SNP- and gene-based methods of analysis, we identified a strong (odds ratio = 13.87) and significant (P value = 1.33E − 11) association of an SNP in the NCK2 gene on chromosome 2 with opiates addiction in African-origin men. Codependence analysis also identified a genome-wide significant association between NCK2 and comorbidity of substance dependence (P value = 3.65E − 08) in African-origin men. Furthermore, we observed that the association between the NCK2 gene (P value = 3.12E − 10) and opiates addiction reached the gene-based genome-wide significant level. In summary, our findings provided the first evidence for the involvement of NCK2 in the susceptibility to opiates addiction and further revealed the racial and gender specificities of its impact.
Highlights
Substance dependence is believed to result from a combination of genetic and environmental factors
The samples were collected from three large-scale genome-wide association studies: Collaborative Study on the Genetic of Alcoholism (COGA), the Family Study of Cocaine Dependence (FSCD), and the Collaborative Genetic Study of Nicotine Dependence (COGEND) [16, 44, 55, 56]
For the gene-based analysis, we used the open-source tool: Knowledge-Based Mining System for Genome-Wide Genetic Studies (KGG, version 2.0)—based on the single nucleotide polymorphisms (SNPs) association test results and linkage disequilibrium (LD) files produced by PLINK
Summary
Substance dependence is believed to result from a combination of genetic and environmental factors. Paulozzi et al in 2006 reported that the number of deaths which involved prescription opioid analgesics increased from 2,900 in 1999 to at least 7,500 in 2004, an increase of 160% in just 5 years [5]. All available evidence indicated that the increasing numbers of deaths are significantly correlated to the increasing use of prescription drugs, especially opioid painkillers, among people during the working years of life. Genes are believed to be a major factor, it is most likely that there are multiple genes as well as geneenvironment interactions. For this reason, understanding the genetic mechanisms behind vulnerability to drug addiction is critical to improve the quality of overall health and life
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