Abstract
Addictions are chronic relapsing/remitting disorders with enormous repercussions at the individual and societal level. Heritabilities of addictions range from 0.39 to 0.72. Therefore it is essential to identify genetic vulnerability factors to clarify etiology and to develop individualized prevention and treatment strategies.
Complex disorders are characterized by the interplay of genetic and environmental factors. We review genomic approaches that are being integrated to advance our understanding of that interface. For addictions involving abused substances, gene-environment interactions can occur at the pharmacokinetic and pharmacodynamic level via modulations of neuronal pathways involved in behavioral control, reward and stress resiliency. Animal models allow the manipulation of environment and genes to reveal associations between addiction-related behaviors and neurobiological phenotypes that are inaccessible in humans.
Genome-wide analyses, including whole-genome linkage and association, allow for hypothesis-free mapping of disease-causing loci and measurement of effects of environmental exposure. Deep sequencing is augmenting the catalog of rare variants essential to understand the genetic heterogeneity of addiction. Recently intermediate phenotypes have provided a bridge between functional alleles and complex phenotypes and offer the same opportunity in genome-wide analyses. Environmental effects may be captured in part via epigenetic modifications and changes in gene expression. The analysis of these effects is a long-lasting challenge, but immediate benefits may be realized.
Keywords: Review, addiction, heritability, genomics, gene x environment, intermediate phenotypes
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