title: A genome-wide association study of a sustained pattern of antidepressant response.
abstract: Genome-wide association studies (GWAS) have failed to replicate common genetic variants associated with antidepressant response, as defined using a single endpoint. Genetic influences may be discernible by examining individual variation between sustained versus unsustained patterns of response, which may distinguish medication effects from non-specific, or placebo responses to active medication. We conducted a GWAS among 1116 subjects with Major Depressive Disorder from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who were characterized using Growth Mixture Modeling as showing a sustained versus unsustained pattern of clinical response over 12 weeks of treatment with citalopram. Replication analyses examined 585 subjects from the Genome-based Therapeutic Drugs for Depression (GENDEP) trial. The strongest association with sustained as opposed to unsustained response in STAR*D involved a single nucleotide polymorphism (SNP; rs10492002) within the acyl-CoA synthetase short-chain family member 3 gene (ACSS3, p-value=4.5×10(-6), odds ratio=0.61). No SNPs met our threshold for genome-wide significance. SNP data were available in GENDEP for 18 of the top 25 SNPs in STAR*D. The most replicable association was with SNP rs7816924 (p=0.008, OR=1.58); no SNP met the replication p-value threshold of 0.003. Joint analysis of these 18 SNPs resulted in the strongest signal coming from rs7816924 (p=2.11×10(-7)), which resides in chondroitin sulfate N-acetylgalactosaminyltransferase 1 gene (CSGALNACT1). An exploratory genetic pathway analysis revealed evidence for an involvement of the KEGG pathway of long-term potentiation (FDR=.02). Results suggest novel genetic associations to sustained response.
authors.affiliation: Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, USA. amhunter@ucla.edu
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Hunter
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Leuchter
authors.forename: Robert A
authors.initials: RA
authors.lastname: Power
authors.forename: Bengt
authors.initials: B
authors.lastname: Muthén
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McGrath
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: Ian A
authors.initials: IA
authors.lastname: Cook
authors.forename: Holly A
authors.initials: HA
authors.lastname: Garriock
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.forename: Steven P
authors.initials: SP
authors.lastname: Hamilton
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D016001:Confidence Intervals; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D016017:Odds Ratio; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D000928:Antidepressive Agents
keywords: Antidepressant; Citalopram; GENDEP; Genetics; Growth mixture modeling; STAR*D