title: Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D.
abstract: Affecting about 1 in 12 Americans annually, depression is a leading cause of the global disease burden. While a range of effective antidepressants are now available, failure and relapse rates remain substantial, with intolerable side effect burden the most commonly cited reason for discontinuation. Thus, understanding individual differences in susceptibility to antidepressant therapy side effects will be essential to optimize depression treatment. Here we perform genome-wide association studies (GWAS) to identify genetic variation influencing susceptibility to citalopram-induced side effects. The analysis sample consisted of 1762 depression patients, successfully genotyped for 421K single-nucleotide polymorphisms (SNPs), from the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study. Outcomes included five indicators of citalopram side effects: general side effect burden, overall tolerability, sexual side effects, dizziness and vision/hearing side effects. Two SNPs met our genome-wide significance criterion (q<0.1), ensuring that, on average, only 10% of significant findings are false discoveries. In total, 12 additional SNPs demonstrated suggestive associations (q<0.5). The top finding was rs17135437, an intronic SNP within EMID2, mediating the effects of citalopram on vision/hearing side effects (P=3.27 × 10(-8), q=0.026). The second genome-wide significant finding, representing a haplotype spanning ∼30 kb and eight genotyped SNPs in a gene desert on chromosome 13, was associated with general side effect burden (P=3.22 × 10(-7), q=0.096). Suggestive findings were also found for SNPs at LAMA1, AOX2P, EGFLAM, FHIT and RTP2. Although our findings require replication and functional validation, this study demonstrates the potential of GWAS to discover genes and pathways that potentially mediate adverse effects of antidepressant medications.
authors: Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, School of Pharmacy, Richmond, VA 23298-0581, USA. deadkins@vcu.edu
authors: D E
authors: DE
authors: Adkins
authors: S L
authors: SL
authors: Clark
authors: K
authors: K
authors: Åberg
authors: J M
authors: JM
authors: Hettema
authors: J
authors: J
authors: Bukszár
authors: J L
authors: JL
authors: McClay
authors: R P
authors: RP
authors: Souza
authors: E J C G
authors: EJ
authors: van den Oord
mesh_terms: D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects*; D015283:Citalopram / Q000009:adverse effects*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics; D005163:Factor Analysis, Statistical; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram