Abstract
BackgroundClassical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS) have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction.ResultsHere, we performed a meta-analysis of addiction candidate gene association studies and GWAS to investigate possible functional mechanisms associated with addiction susceptibility. From meta-data retrieved from 212 publications on candidate gene association studies and 5 GWAS reports, we linked a total of 843 haplotypes to addiction susceptibility. We mapped the SNPs in these haplotypes to functional and regulatory elements in the genome and estimated the magnitude of the contributions of different molecular mechanisms to their effects on addiction susceptibility. In addition to SNPs in coding regions, these data suggest that haplotypes in gene regulatory regions may also contribute to addiction susceptibility. When we compared the lists of genes identified by association studies and those identified by molecular biological studies of drug-regulated genes, we observed significantly higher participation in the same gene interaction networks than expected by chance, despite little overlap between the two gene lists.ConclusionsThese results appear to offer new insights into the genetic factors underlying drug addiction.
Highlights
Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances
We further assessed the variants using criteria established by the Human Genome Epidemiology Network (HuGENet) Road Map [24] that was recently proposed for assessing cumulative evidence from genetic association studies
When we compare the addiction susceptible genetic variants linked by candidate gene association studies and genome-wide association studies (GWAS), we found that the GWA arrays included probes for three polymorphisms showing significant summary odds ratio of the addiction susceptibility
Summary
Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS) have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction. Genetic association studies, including candidate gene studies and genome-wide association studies (GWAS), can provide insights into the genetic background of this neurobiological and behavioral disorder. Using these approaches, more than 800 publications during the past three decades have reported genomic loci and/or specific genetic variants that have been associated with susceptibility to drug addiction. To date there have been only modest genome-scale efforts to study the molecular mechanisms of addiction-associated genetic variants. The relative contributions of different molecular mechanisms remain largely unknown
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