Pharmacogenomic study of side-effects for antidepressant treatment options in STARD

• Published in: Psychological medicine Vol. 42; no. 6; pp. 1151 - 1162
• Main Authors: Clark, S. L., Adkins, D. E., Aberg, K., Hettema, J. M., McClay, J. L., Souza, R. P., van den Oord, E. J. C. G.
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.06.2012
• Subjects: Adult and adolescent clinical studies; Antidepressant drugs; Antidepressants; Antidepressive Agents - adverse effects; Biological and medical sciences; bupropion; Bupropion - adverse effects; CHL1 protein; Citalopram - adverse effects; Depression; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - genetics; Dizziness; Drug therapy; Drug-Related Side Effects and Adverse Reactions - classification; Drug-Related Side Effects and Adverse Reactions - genetics; Factor Analysis, Statistical; Genes; Genetic diversity; Genetic Predisposition to Disease; Genetic variation; Genome-Wide Association Study; Genomics; Humans; Individual differences; Linear Models; Linkage Disequilibrium - genetics; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - physiology; Mood disorders; Neuropharmacology; Pharmacogenetics; pharmacogenomics; Pharmacology; Pharmacology. Drug treatments; Phenotype; Polymorphism, Single Nucleotide - genetics; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Replication; Sexual Dysfunction, Physiological - chemically induced; Sexual Dysfunction, Physiological - genetics; Side effects; Single-nucleotide polymorphism; Susceptibility; Treatment Outcome; Validation; Vision; Depression; STARD; pharmacogenomics; side-effects; single nucleotide polymorphisms; genome-wide association study; Mood disorder; Psychotropic; Toxicity; Genetic determinism; Treatment; Genetics; Antidepressant agent; Single nucleotide polymorphism
• ISSN: 0033-2917; 1469-8978
• DOI: 10.1017/S003329171100239X

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