The observation of familial aggregation of mood disorders has promoted the search for genetic factors related to the neurobiological underpinnings of major depressive disorder (MDD) (McGuf˜n and Katz 1989). Heritability is at least modest and has been estimated to range between 31% and 42% according to twin studies (Sullivan et al. 2000). Despite numerous reports of associations between candidate genes and MDD, results of clinical association studies are characterized by a high level of inconclusiveness (Levinson 2006; Burmeister et al. 2008), and several enthusiastically acclaimed ˜ndings (Lesch et al. 1996; Caspi et al. 2003) have recently been questioned (Risch et al. 2009; Munafo et al. 2009). Similarly, attempts to establish a clinical decision tree for therapeutic drug interventions or diagnostics based on genetics have shown to be only of modest clinical relevance (Schosser and Kasper 2009; Kato and Serretti 2008). Similar discouraging ˜ndings have been made in other common disorders ranging from schizophrenia to hypertension. This is in stark contrast to successful gene assignments in monogenetic diseases that are subject to Mendelian inheritance, for example, Huntington disease (Risch 2000). Several aspects are held responsible

4.1 Introduction ............................................................................................................................ 75 4.2 Bridging the Gap between Genotype and Phenotype ............................................................ 76 4.3 Techniques Used in Imaging Genetics ...................................................................................77 4.4 Depression-Related Brain Circuits .........................................................................................77