Endophenotypes of adolescent substance use

Adolescence is a critical developmental period regarding exposure to substances. Therefore, it is important to be able to identify those adolescents who are most vulnerable to substance abuse in the (near) future. Genetic susceptibility is one important factor that underlies individual vulnerability. For complex multifactorial disorders such as substance abuse, the identification of susceptibility genes may be substantially aided by using quantitative intermediate phenotypes, or endophenotypes, instead of dichotomized clinical variables (Gottesman & Gould 2003). These endophenotypes reflect neurobiological pathways to substance abuse. Our study will focus on two such pathways. Several studies suggest a shared underlying etiology across a spectrum of disinhibitory disorders, including substance abuse. A first pathway is therefore represented by these underlying cognitive dysfunctions which can result in behavioural disinhibition. Cognitive problems, in particular behavioural disinhibition is related to alterations in the prefrontal cortex activity, which may result in reduced cognitive control. Two endophenotypes for this pathway are: (1) The P3 component of the Event-Related Potential (ERP), which is associated with attentional allocation and context updating processes of working memory and involves the activation of inhibitory processes (Frederick & Iacono 2006). The P3 component has proven successful in identifying genes associated with alcohol dependence (Dick et al 2006); (2) reward-associated decision-making skills which have been associated with substance abuse in adults. A second pathway relates to individual differences in stress physiological responses, which may increase the risk of abusing substances, and may also explain the relation between several forms of psychopathology, and substance abuse. Two endophenotypes for this pathway are an altered stress reactivity of (3) the hypothalamic-pituitary-adrenal (HPA) axis and (4) the autonomic nervous system (ANS) in substance abusers. These four endophenotypic characteristics will be studied in a large sample of adolescents, and will be associated with substance use and DNA polymorphisms, to analyse the pathway from genotype via endophenotype to phenotype. A general population sample of 500 13-to-18-year-olds will participate in this study. Our study sample will be enriched by a high risk sample of n=100 adolescents, who have at least one parent with a substance use disorder. The combination of different methods in this proposal to study substance use, and the possibility to work with a large adolescent study composed of a general population study and a high-risk sample, has the potential for melding complementary approaches for investigating the multifactorial nature of substance use in adolescence.