However, this finding does indicate, as the large literature on familial

MD confirms (reviewed in Rutter et al., 1999 and Sullivan et al., 2000), that clinical differences exist between those with and those without a family history of MD. Distinguishing features are relatively nonspecific: those with a family history of MD have more clinically severe illness, tend to present at an earlier age, and suffer higher rates of recurrence (Kendler et al., 1994, Kendler et al., 1999, Lieb et al., 2002 and Weissman et al., 2006). Environmental influences are also likely to stratify MD. Evidence from twin studies (Kendler et al., 1995a, Kendler et al., 2004 and Silberg et al., 2001) indicate that genetic risk factors for MD not only BTK inhibitor alter average risk but also impact on sensitivity to the depressogenic effects of environmental adversities, particularly various forms of childhood maltreatment and recent stressful life events. The finding of increased genetic susceptibility to environmental stressors, or in short a gene by environment interaction, suggests the possibility of subdividing MD on the basis of

environmental effects: theoretically genetic effects will be HSP inhibitor more homogeneous, relatively larger, and easier to detect in populations with clearly defined exposures. While twin studies have shown that aggregate genetic risk factors for MD interact with stressful events, in recent years the field has been preoccupied with one

of the many possible ways in which this effect might be explained at the molecular level. The dispute is whether or not the serotonin transporter 5-HTTLPR variant is involved in a gene by environment interaction. The original study was carried out on almost a longitudinal cohort in New Zealand, and empirical literature dealing with whether that finding is robust, and replicable, is unclear and considerably polarized ( Caspi et al., 2010, Kaufman et al., 2010 and McGuffin et al., 2011). Two meta-analyses found no evidence for an interaction (Munafò et al., 2009 and Risch et al., 2009), while one meta-analysis concluded that there was an effect (Karg et al., 2011). The difference lies in the way studies were selected for the meta-analyses. The authors of the positive GxE meta-analysis take the view that the effect of GxE is broad: “rather than focus on a specific class of studies, we sought to perform a meta-analysis on the entire body of work assessing the relationship between 5-HTTLPR, stress, and MD” ( Karg et al., 2011).