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

Background: Understanding individual differences in susceptibility to antidepressant therapy side-effects is essential to optimize the treatment of depression.

Method: We 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.

Results: Thirty-four SNPs satisfied this criterion. The top finding indicated that 10 SNPs in SACM1L mediated the effects of bupropion on sexual side-effects (p = 4.98 × 10(-7), q = 0.023). Suggestive findings were also found for SNPs in MAGI2, DTWD1, WDFY4 and CHL1.

Conclusions: Although 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.