The death(s) of close friends and family moderate genetic influences on symptoms of major depressive disorder in adolescents.

Genetically-informed research has clearly support a moderate role (31-42%) for genetic influences on Major Depressive Disorder (MDD) (Sullivan et al., 2000), results that appear to hold across the lifespan (Burt, 2009). For example, Burt (2009) meta-analyzed 33 twin and adoption studies of child and adolescent MDD/depression. In adolescence, 39% of the variance in depression was accounted for by genetic influences. The environment also plays an important role, however, accounting for the remainder of the phenotypic variance. Indeed, there are several specific environmental risks that may contribute to the development of MDD. Among those most studied are stressful life events (SLEs). These include independent SLEs unrelated to the individual's behavior (e.g., the death of a loved one or a natural disaster) and dependent SLEs that could potentially be related to some behavior of the person (e.g., divorce/relationship stressors, unemployment), a distinction first made by Brown & Harris (1978). Both types of SLEs have been associated with the onset of depression in adolescents (Goodyer et al., 2000; Ge et al., 2001), although the association is somewhat stronger for dependent SLEs (Kendler et al., 1999). Research also suggests that the number of SLEs one experiences may be an important predictor of later depressive episodes (Kendler et al., 1998). Indeed, it has been suggested that multiple exposures to such experiences could lower the threshold needed for an individual to enter a depressive state (Kendler et al., 2001). In short, both genetic influences and SLEs are important predictors of MDD. However, their influences may not be additive. Instead, it may be the case that SLEs are linked to depression in part because they moderate the expression of genetic predilections towards depression, a phenomenon referred to as a gene-environment interaction (GxE). Eaves et al. (2003), for example, argued that genetic risk “for depression” may actually be reflective of sensitivity to environmental stressors. Consistent with this idea, more recent work has indicated that, as genetic risk to developing depression increases, so does the depressogenic susceptibility to stressful life events (Lau & Eley, 2008). Similarly, Silberg et al. (2001) found that genetic effects on depression were significantly greater in adolescents who had experienced stressful life events compared to those who had not. Not all findings are consistent with the possibility of GxE, however. Hicks et al. (2009) found that stressful life events increased non-shared environmental influences on internalizing symptoms, but did not moderate genetic effects. These inconsistencies across studies indicate that additional GxE studies of SLEs and MDD are needed before any firm conclusions can be drawn. Future studies should also seek to address the various limitations of prior GxE work. For example, GxE studies to date have relied exclusively on molecular genetic and/or twin methodologies (to our knowledge). Indeed, we know of no adoption studies that have sought to identify GxE in depression. Constructive replication using other sorts of genetically-informative designs (like an adoption design) would thus constitute an important addition to prior work, as it would confirm that prior results are not confined to specific methodologies. Another, arguably more important, limitation of examinations of GxE with SLE's is that dependent SLEs are unlikely to be genetically-independent of depression (as discussed in Silberg et al., 2001), a phenomenon referred to as a gene-environment correlation (rGE). In particular, individuals may “have a stable tendency to select themselves into situation with a big probability of producing SLEs” (Kendler et al., 1999, pg. 838), and this tendency may reflect genetic risk for depression (Kendler & Karkowski-Shuman, 1997; Silberg et al., 1999; Kendler et al., 1999). For example, Williamson et al. (1995) found that, when comparing adolescents with depression to normal controls, the proportion of dependent SLEs (out of the total number of SLEs) experienced was greater, even though the total number of SLEs was comparable between groups. There was no significant difference in the number of independent SLEs. This suggests that, even when experiencing similar numbers of SLEs, depressed individuals may be more likely to select themselves into stressful circumstances as compared to their healthy peers. This effect has also been demonstrated by Rudolph & Hammen (1999). These sorts of rGE's (referred to specifically as active rGE) are particularly troublesome in GxE research (Moffitt et al., 2005). In particular, if SLEs stem in part from genes common to MDD (or if genes for SLEs interact with genes for depression), then the potentiation of genetic influences at high levels of “environmental” risk could be a reflection of rGE processes, rather than true GxE. Several prior studies have attempted to address this confound by modeling genetic overlap between depression and dependent SLE's (Eaves eta al., 2003; Lau & Eley, 2008). However, another, more convincing approach is to circumvent active rGE via the examination of independent SLEs, which are, by definition, random “bad luck” events unassociated with the individual's behavior (and thus his or her genetic risk; Bemmels et al., 2008). The present study sought to address these concerns, and thereby provide additional evidence of the presence or absence of GxE between SLEs and MDD symptoms. We specifically focused on the death(s) family and/or close friends, examining the number of deaths experienced. This SLE represents a promising potential moderator, as it has a potent relationship with depression in adolescents (Harrison & Harrington, 2001). Moreover, the deaths of friends/family are generally considered independent of the individual's behaviors, and thus etiological moderation by number of deaths experienced should be largely free of active rGE confounds. We also made use of a large sample of adoptive and biological siblings between the ages of 10 and 20, thereby clarifying whether previously reported evidence of GxE extends to other sorts of genetically informed designs. Positive evidence of GxE in the current study would thus serve to both constructively replicate and extend prior findings of GxE between SLEs and MDD symptoms.