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; 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 (fig. S4b). In animal models, hippocampal NAA can be decreased by chronic stress (Czeh et al., 2001; Li et al., 2008). Thus, a genetic predisposition towards 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).
