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.