31. Through replication in a meta-analysis across six independent samples, confidence in the robustness of the reported disease association is considerable. This

finding is all the more important as prior GWA studies failed to identify susceptibility Antidiabetic Compound Library manufacturer variants of MDD on a genome-wide supported level of significance ( Lewis et al., 2010 and Shi et al., 2011). As is often the case, the identified polymorphism in the Kohli study maps to a chromosomal “desert area” outside any annotated gene, which complicates the process of finding a biologically meaningful interpretation of the finding. This highlights the crucial relevance of implementing multiple, interrelated intermediate phenotype studies to help assign a function to the initial genetic result. Based on the relative proximity, the authors hypothesized a regulatory effect of the variant on the expression of a gene of the solute carrier 6 family (SLC6A15), a sodium-dependent high-affinity transporter for large amino acids in the central nervous system ( Bröer et al., 2006). In line with their expectations, the authors demonstrate a significant decrease in expression of the full-length Ixazomib molecular weight SLC6A15 mRNA isoform in rs1545843 risk allele carriers by using a valuable resource, human premortem hippocampal

tissue. The access to this material is especially useful because prior evidence relates stress-induced impairments in hippocampal neuroplasticity to the expression of cognitive and affective deficits in MDD. Notably, these processes have been convincingly linked to alterations in glutamate neurotransmission, which is critical for the neuroplasticity and anatomy of the hippocampus

(Fuchs et al., 2004). Interestingly, proline, a precursor for glutamate synthesis, is the substrate with the highest affinity for the SLC6A15 transporter. Endonuclease Thus, these findings may indicate a potential risk mechanism linking SLC6A15 genotype and environmental stressors to limbic dysregulation in glutamate neurotransmission and ultimately to psychopathology. To probe the theory of a modulation of SLC6A15 function by environmental factors such as chronic stress, the authors expand their analysis to the examination of gene expression in the hippocampus of an established mouse model of stress vulnerability and resilience. In line with their hypothesis, Kohli et al. (2011) demonstrate a significant and specific reduction of SLC6A15 mRNA expression in stress-susceptible mice. Finally, by adding yet two other intermediate phenotype levels, Kohli et al. (2011) extend their scope from genetic association and gene expression to in vivo biomarkers of the human brain and examine the impact of the identified susceptibility variant on hippocampus anatomy and neurochemistry.