Pharmacogenomic study of side-effects for antidepressant treatment options in STAR*D

Abstract

BackgroundUnderstanding individual differences in susceptibility to antidepressant therapy side-effects is essential to optimize the treatment of depression.MethodWe performed genome-wide association studies (GWAS) to search for genetic variation affecting the susceptibility to side-effects. The analysis sample consisted of 1439 depression patients, successfully genotyped for 421K single nucleotide polymorphisms (SNPs), from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Outcomes included four indicators of side-effects: general side-effect burden, sexual side-effects, dizziness and vision/hearing-related side-effects. Our criterion for genome-wide significance was a prespecified threshold ensuring that, on average, only 10% of the significant findings are false discoveries.ResultsThirty-four SNPs satisfied this criterion. The top finding indicated that 10 SNPs inSACM1Lmediated the effects of bupropion on sexual side-effects (p=4.98×10−7,q=0.023). Suggestive findings were also found for SNPs inMAGI2,DTWD1,WDFY4andCHL1.ConclusionsAlthough our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes and pathways that could mediate adverse effects of antidepressant medication.