As with other complex human behavioral disorders, risk gene identification has been difficult—with one recent major success in identifying nicotinic receptor variants that affect risk for nicotine dependence. We are still learning how to optimally measure SUDs for genetic studies. It is not clear that our current diagnostic formulations are optimal. Important potential advances can also be made in the assessment of drug consumption, as is well illustrated by the substantial gain in the power to detect risk genes for smoking when measuring the long-lasting nicotine metabolite cotinine. But although genetic epidemiologic methods are giving us an increasingly accurate map of broad causal pathways to SUDs, gene discovery will be needed to identify the specific biological systems involved. Some of these variants will be in systems that might have been predicted a priori (key degradative enzymes and receptors), but most will not be. The impact of an individual genetic variant on SUD risk is likely to be small. Identifying these risk genes and understanding their modes of action will require large and carefully assessed clinical samples, innovations in the statistical analysis of such data and strong interactions between these human studies and work in model organisms.
