Additional nonannotated transcripts, as described in the ENCODE pilot project in regions of the genome previously thought

to be transcriptionally silent ( Birney et al., 2007), might also be selleck products functionally relevant for this association. The imaging genomics results provide evidence that the associated SNPs and related functional effects on SLC6A15 expression might be of relevance for the integrity of brain neurocircuits shown to be important in MD ( Frodl et al., 2002). We found lower total hippocampal volumes, particularly of the cornu ammonis, in risk genotype carriers of the patient—but not the control—group, indicating a higher vulnerability to the well-documented effects of recurrent depressive episodes on hippocampal volume ( Frodl et al., 2002 and Videbech and Ravnkilde, 2004). Further support for the detrimental effects of the risk allele on neuronal integrity in this brain region came from 1H-NMR spectroscopy. We noted that

healthy risk allele carriers exhibited lower hippocampal NAA compared to non-risk allele carriers. Reduced hippocampal NAA has been reported for different psychiatric disorders and was also decreased in currently depressed unipolar patients in this study ( Figure S4b). In animal models, hippocampal NAA can be decreased by chronic stress ( Czéh et al., 2001 and Li et al., PR-171 concentration 2008). Thus, a genetic predisposition toward lower hippocampal NAA, similar to a condition induced by chronic stress experiments, may impair an individual’s resilience to stress which is a risk factor for MD ( Wang, 2005). While the genetic association

data pointed most strongly to rs1545843, gene expression and imaging data association were strong with both tag-SNPs of the locus, rs1545843 and rs1031681. In healthy subjects, genotype effects on hippocampal neurochemistry were more prominent for rs1031681 compared Histamine H2 receptor with rs1545843, both in terms of effects on NAA and Glx and in terms of robustness toward multiple test correction. This is an indication that both SNPs tag the likely underlying functional variants that still remains to be identified. To this aim, deep-sequencing analyses are currently underway. Together with the demonstrated downregulation of SLC6A15 expression in stress-susceptible mice, human gene expression and imaging data support a role for hippocampal SLC6A15 function in stress sensitivity and the pathophysiology of MD. This would be in line with a proposed role of the SLC6A15 transporters in neuronal metabolism and the provision of substrates for neurotransmitters, and specifically glutamate synthesis ( Bröer et al., 2006).