Linking human and animal addiction genetics - a role for human genetic association studies

The historical direction of cross-species genetic translation has been from model organism to human. Biological mechanisms with clear genetic influence on a behavioral phenotype are discovered and validated in mice, for... [ view full abstract ]

The historical direction of cross-species genetic translation has been from model organism to human. Biological mechanisms with clear genetic influence on a behavioral phenotype are discovered and validated in mice, for example, but that same gene in humans typically does not harbor variation of relevance to the behavior in humans. On the other hand, the vast majority of genetic variants associated with behavioral traits in humans often have no obvious functional relationship to the behavior in question. I will describe a program of research on the human side, where through a community effort we have discovered hundreds of genetic loci associated with alcohol and nicotine use in humans and are now attempting to use deep whole genome sequencing to fine map these loci to discover rare variants with potentially large effect. However, no matter how large the genetic association study or how deep the sequencing, it remains extremely difficult to characterize the functional consequence and mechanism of action, of the associated variants, whether at the cellular, physiological, or behavioral level. I will recommend that one solution is greater collaboration with scientists investigating behavioral genetics in animal models. Substance use may represent an especially fertile testing ground for such collaborations, given the apparent phenotypic similarity between human and animal substance use and addiction.