The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response.

Biernacka JM1, Sangkuhl K2, Jenkins G3, Whaley RM2, Barman P3, Batzler A3, Altman RB4, Arolt V5, Brockmöller J6, Chen CH7, Domschke K8, Hall-Flavin DK9, Hong CJ10, Illi A11, Ji Y12, Kampman O13, Kinoshita T14, Leinonen E15, Liou YJ10, Mushiroda T16, Nonen S17, Skime MK9, Wang L12, Baune BT18, Kato M14, Liu YL19, Praphanphoj V20, Stingl JC21, Tsai SJ10, Kubo M16, Klein TE2, Weinshilboum R12.

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Abstract

Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. 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. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (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). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.