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.
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.
Authors: Holly A Garriock; Jeffrey B Kraft; Stanley I Shyn; Eric J Peters; Jennifer S Yokoyama; Gregory D Jenkins; Megan S Reinalda; Susan L Slager; Patrick J McGrath; Steven P Hamilton Journal: Biol Psychiatry Date: 2010-01-15 Impact factor: 13.382
Authors: Scott A Bull; Enid M Hunkeler; Janelle Y Lee; Clayton R Rowland; Todd E Williamson; Joseph R Schwab; Stephen W Hurt Journal: Ann Pharmacother Date: 2002-04 Impact factor: 3.154
Authors: E Link; S Parish; J Armitage; L Bowman; S Heath; F Matsuda; I Gut; M Lathrop; R Collins Journal: N Engl J Med Date: 2008-07-23 Impact factor: 91.245
Authors: Michael F Berger; Michael S Lawrence; Francesca Demichelis; Yotam Drier; Kristian Cibulskis; Andrey Y Sivachenko; Andrea Sboner; Raquel Esgueva; Dorothee Pflueger; Carrie Sougnez; Robert Onofrio; Scott L Carter; Kyung Park; Lukas Habegger; Lauren Ambrogio; Timothy Fennell; Melissa Parkin; Gordon Saksena; Douglas Voet; Alex H Ramos; Trevor J Pugh; Jane Wilkinson; Sheila Fisher; Wendy Winckler; Scott Mahan; Kristin Ardlie; Jennifer Baldwin; Jonathan W Simons; Naoki Kitabayashi; Theresa Y MacDonald; Philip W Kantoff; Lynda Chin; Stacey B Gabriel; Mark B Gerstein; Todd R Golub; Matthew Meyerson; Ashutosh Tewari; Eric S Lander; Gad Getz; Mark A Rubin; Levi A Garraway Journal: Nature Date: 2011-02-10 Impact factor: 49.962