Abstract
Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction; however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction by single-gene strategies, microrray, proteomics, or genetic studies. We identified 1,500 human addiction-related genes and developed KARG (http://karg.cbi.pku.edu.cn), the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. We then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways which may underlie shared rewarding and addictive actions, including two new ones, GnRH signaling pathway and gap junction. We connected the common pathways into a hypothetical common molecular network for addiction. We observed that fast and slow positive feedback loops were interlinked through CAMKII, which may provide clues to explain some of the irreversible features of addiction.
Highlights
Drug addiction, defined as ‘‘the loss of control over drug use, or the compulsive seeking and taking of drugs despite adverse consequences,’’ has become one of the most serious problems in the world [1]
It has been estimated that genetic factors contribute to 40%–60% of the vulnerability to drug addiction, and environmental factors provide the remainder [2]
It has been estimated that genetic factors contribute to 40%– 60% of the vulnerability to drug addiction, and environmental factors provide the remainder
Summary
Drug addiction, defined as ‘‘the loss of control over drug use, or the compulsive seeking and taking of drugs despite adverse consequences,’’ has become one of the most serious problems in the world [1]. Recent high-throughput expression-profiling technologies such as microarray and proteomics analyses identified candidate genes and proteins whose expression level changed significantly among different states in addiction [4,5]. Genetic studies such as animal Quantitative Trait Locus (QTL) studies, genetic linkage studies, and population association studies identified chromosomal regions that may contribute to vulnerability to addiction [6,7,8]. Systematic and statistical analysis of the genes and the underlying pathways may provide a more complete picture of the molecular mechanism underlying drug addiction
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