The first GWAS of depression was published in 2009 and included 1,738 cases and 1,802 controls. Although no SNPs reached genome-wide significance, 11 of the top 200 SNPs were found in a 167 kilobase (kb) region overlapping the gene PCLO (piccolo presynaptic cytomatrix protein), which is involved in establishing active synaptic zones and synaptic vesicle tracking.43 In several subsequent studies,44,49,58 investigators found mixed evidence regarding the association of PCLO SNPs and MDD. In the first study to report a genome-wide significant association for depression, Kohli and colleagues50 found support for a recessive effect of a SNP (rs1545843) in the gene SLC6A15 (solute carrier family 6, neutral amino acid transporter, member 15) that is involved in transporting neutral amino acids. They provided additional evidence in support of this association by demonstrating that risk alleles were correlated with reduced SLC6A15 expression in hippocampal tissue (taken from individuals undergoing surgery for epilepsy) and reduced hippocampal volume and neuronal integrity using neuroimaging. Mice susceptible to chronic stress were also found to have reduced hippocampal SLC6A15 expression. Of note, however, this locus has not emerged as a prominent finding in subsequent depression GWAS (described below).
