Adolescents with a short allele of the 5-HTTLPR are at increased risk for substance use initiation in the context of early life stress (Kaufman, et al., 2007), with the effect stronger among adolescents experiencing lower levels of supportive parenting (see Brody et al., 2009). Among those participating in SAAF, the interaction of participation in the program with presence of the “s” allele resulted in earlier onset of substance use among “s” allele carriers who were in the control group relative to “s” allele carriers receiving SAAF or non-carriers in either group. More recent evidence suggests that “s” allele carriers may continue to be at elevated risk for onset of additional risky behavior if they initiate substance use. In particular, among youth initiating early substance use, 5-HTTLPR was found to interact with early substance use initiation such that carriers of the “s” allele who were early initiators were also more likely to initiate risky sexual behavior two years later (Kogan et al., 2010). Accordingly, carrying the “s” allele may be involved in further amplification of problems associated with early substance use initiation, potentially amplifying effects on affiliation related biomarkers, leading to the pattern of multiple moderation illustrated in Figure 1.