G. The genetic architecture for substance dependence in individuals What about the genetic architecture for substance dependence in individuals? Both “between locus” heterogeneity and “within locus” heterogeneity are likely. If we follow the implications of polygenic genetic models for addiction vulnerability, we can infer that each dependent individual might even display a nearly-distinct set of risk-elevating or risk-reducing allelic variants. As an illustrative example, we might postulate that a) an individual must display at least 50 risk alleles to robustly elevate his/her likelihood of acquiring a substance dependence disorder and b) there are 200 genes that contain common allelic variants that can augment addiction risk. Under such circumstances, it is easy to see that the exact genetic recipe for addiction vulnerability found in one addicted individual might be replicated in only a relatively few other addicted individuals. Such an underlying genetic architecture would be consistent with the failure of linkage-based methods to provide reproducible results in addictions, since linkage relies on identifying consistent patterns in the ways that specific DNA markers and phenotypes move through many families that display high densities of the disorder.
