This further supports SLC6A15 as the gene of interest within this locus. The reduction of SLC6A15 expression in CA1 could be validated by in situ hybridization in nine stress-susceptible versus nine Alectinib chemical structure stress-resilient mice ( Figures 6A and 6B). Moreover, a significant reduction in SLC6A15 expression could also be observed in the dentate gyrus of stress susceptible animals ( Figures 6C and 6D). The demonstrated downregulation of SLC6A15 expression in stress-susceptible mice, most prominent in the CA1 region of the hippocampus, suggests SLC6A15 to play a role in long-term effects of chronic stress on neuronal circuits and is in accordance with the human MD risk genotype-dependent

effects, assayed by in vivo volumetry, which were also strongest in the CA subregion of the hippocampus. We performed a GWA study, with replication of the top hit and genome-wide significant association in the meta-analysis across a total of 4,088 patients and 11,001 controls, including one sample from a different ethnic background. Together with gene expression data, neuroimaging correlates and evidence

from a mouse model of chronic stress our results point toward SLC6A15, a neuronal amino acid transporter, Epacadostat chemical structure as a candidate gene in the pathophysiology of major depression. Even though the direction of the association of rs1545843 with depression and depressive symptoms was the same in all samples with nongeriatric depression, the effect sizes were heterogeneous, with a much larger effect in the discovery sample (OR = 2.8 for the recessive model) as compared to the other samples with odds ratios ranging

from 1.18 to 1.61. The strong association and low p value in the discovery sample is probably due to the “winners’ curse,” but this phenomenon has also been observed below for other, now established, disease loci. For example, the association of a SNP in the FGFR2 gene with breast cancer was much stronger in the rather small discovery sample than in any of the subsequent replication samples. However, the direction of the association was consistent and reached a p value of 2e-76 in close to 30,000 cases and controls ( Easton et al., 2007). This indicates that heterogeneous effect sizes with overestimation of the effect in a small discovery sample may still be in agreement with a true signal. In addition to the genome-wide significance ( Dudbridge and Gusnanto, 2008) observed in our study, replication of the effect in samples of different ethnicities, European and African-American, might be a further indicator for a true effect. In addition to replication in independent samples, the functional relevance of the associated locus is supported by results of gene expression analyses in premortem human hippocampus and EBV-transformed lymphoblastoid cell lines of the HapMap individuals (Stranger et al., 2005) and peripheral blood monocytes (Heinzen et al., 2008).