Background Genome-wide association studies are a powerful tool for unravelling the genetic background of complex disorders such as major depression. Methods We conducted a genome-wide association study of 604 patients with major depression and 1364 population based control subjects. The top hundred findings were followed up in a replication sample of 409 patients and 541 control subjects. Results Two SNPs showed nominally significant association in both the genome-wide association study and the replication samples: 1) rs9943849 ( pcombined = 3.24E-6) located upstream of the carboxypeptidase M ( CPM ) gene and 2) rs7713917 ( pcombined = 1.48E-6), located in a putative regulatory region of HOMER1 . Further evidence for HOMER1 was obtained through gene-wide analysis while conditioning on the genotypes of rs7713917 ( pcombined = 4.12E-3). Homer1 knockout mice display behavioral traits that are paradigmatic of depression, and transcriptional variants of Homer1 result in the dysregulation of cortical-limbic circuitry. This is consistent with the findings of our subsequent human imaging genetics study, which revealed that variation in single nucleotide polymorphism rs7713917 had a significant influence on prefrontal activity during executive cognition and anticipation of reward. Conclusion Our findings, combined with evidence from preclinical and animal studies, suggest that HOMER1 plays a role in the etiology of major depression and that the genetic variation affects depression via the dysregulation of cognitive and motivational processes.