GWAS on SSRI treatment outcome in patients with depression: ISPC cohort and meta-analysis

The treatment response to selective serotonin reuptake inhibitors (SSRIs), a major class of antidepressant drugs, varies considerably between patients. The International SSRI PharmacogenomicsConsortium (ISPC) was established with the primary goal of identifying genetic variations that may contribute to SSRI treatment outcome in patients with depressive disorder.  The ISPC includes eight research groups that contributed clinical and genetic data. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites and the results are published in the journal Translational Psychiatry.  Although many top association signals in the ISPC analysis for the primary outcomes percent change in HRSD-17 score and response map to interesting candidate genes (see Table 2 in the article), none were significant at the genome-wide level. The associations did not replicate using data from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression(STAR*D) study. Top association results in the meta-analysis of response based on data from the ISPC, PGRN-AMPS and STAR*D cohorts included SNPs in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4) /VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (p=5.03E-08), and SNPs 5’ upstream of the neuregulin-1 gene, NRG1 (p=1.20E-06).