Gene-environment interplay in internalizing disorders: consistent findings across six environmental risk factors.

Internalizing (INT) disorders (i.e., major depression and anxiety disorders) are the most common forms of mental illness, and the prevalence of these disorders increases dramatically in late adolescence (Hankin et al., 1998; Kessler et al., 2005). Examining mechanisms of risk in late adolescence can provide important insights into their etiology and help curtail later negative outcomes. INT disorders are heritable (Kendler et al., 2003), but are also associated with various environmental risk factors such as stressful life events (Kendler et al., 1995), negative family relationships (Emery, 1982), and poor social support (e.g., friendship quality) (Kessler et al., 1992). Notably, these genetic and environmental risk factors are not independent. For example, persons who exhibit high levels of INT distress experience more stressful life events, and part of this association is genetically mediated (Silberg et al., 1999). Also, there is evidence that individuals at higher genetic risk are more likely to exhibit INT symptoms upon exposure to environmental stressors (Kendler et al., 1995, 2004). While there has been a dramatic increase in the number of studies examining gene-environment (G-E) interplay in psychopathology research in recent years (Thapar et al., 2007), few studies have attempted to integrate findings across multiple disorders and multiple risk factors in an effort to answer fundamental questions regarding general principles of G-E influence in the development of psychiatric disorders. For example, does the mechanism of environmental influence differ for such risk factors as stressful life events, deviant peers, and parenting? Or, is there a general mechanism of environmental influence? Also, are the mechanisms of G-E interplay the same for all forms of psychopathology? For example, are the mechanisms of G-E influence the same or different for INT versus externalizing (EXT) disorders (i.e., antisocial behavior and substance use disorders)? Two G-E mechanisms underlie the etiology of psychiatric disorders. The first process is G-E correlation, and refers to the fact that an individual’s exposure to environmental risk is in part due to his or her personal characteristics, decisions, and behaviors (Moffitt, 2005; Scarr & McCartney, 1983). For example, INT symptoms are associated with negative life events, especially events that are in some way “dependent” on the individual’s behavior such as interpersonal conflict, and these associations are to some extent due to common genetic risk factors (Silberg et al., 1999). G-E correlations also account for the finding that nearly all putatively “environmental” risk factors are to some extent heritable (Kendler & Baker, 2007). G × E interactions are the second process, and refer to the fact that environmental stressors have a greater impact on a subset of individuals who are genetically at high-risk. For example, Kendler et al. (1995) found that adult women inferred to be at high genetic risk based on having a monozygotic (MZ) twin with a lifetime history of major depression were more likely to experience an episode of major depression following stressful life events than women who also experienced stressful events but whose MZ twin had no history of major depression. Similar results were found for adult men and women using scores on neuroticism as an index of genetic risk (Kendler et al., 2004). A few studies with adolescent twins have reported more direct tests of G × E interaction with genetic variance in INT symptoms increasing as a function of environmental stress such as negative life events and family conflict (Eaves et al., 2003; Lau & Eley, 2008; Rice et al., 2006; Silberg et al., 2001). Other analyses in both adult and child/adolescent samples, however, have found that the environmental rather the genetic variance of INT increased in the context of greater environmental adversity (Feinberg et al., 2007; Lau & Eley, 2008; Lau et al., 2007; South et al., 2009; South & Krueger, 2008). Given these somewhat inconsistent findings, we took a more comprehensive approach to delineating G-E interplay in the emergence of INT symptoms by examining a variety of contextual domains in late adolescence that are associated with increased INT symptoms (Gerard & Buehler, 2004). Specifically, we sought to provide a fairly comprehensive assessment of environmental context during late adolescence by including a diverse set of measures that tap important dimensions of psychosocial functioning (Masten et al., 1995). These measures covered the domains of parent-child relationship quality, peer affiliation, academic functioning, and stressful life events. Our approach is based on the premise that general principles of G-E influence on INT would emerge by examining multiple risk factors in the same sample. Also, in a separate analysis, we have examined G-E interplay among the same environmental risk factors and an EXT composite (Hicks et al., in press). Thus, the two studies provide an excellent opportunity to examine convergent and discriminant patterns of G-E interplay by incorporating multiple environmental risk factors and multiple psychopathology constructs. An additional strength of our study was that both the environmental risk factors and INT were assessed using multiple methods and informants providing excellent measurement of the target constructs. Finally, mindful of the fact that a G-E correlation can confound the interpretation of a G × E interaction (Moffitt, 2005; Uher & McGuffin, 2007), we employed sophisticated quantitative twin models that incorporate both processes, thereby accounting for any selection effects (i.e., G-E correlation) in the presence of a G × E interaction (Purcell, 2002).