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 1,116 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.

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

“…Antidepressant drugs can both prevent stress-induced decrease of hippocampal neurogenesis and reverse it (Malberg and Duman 2003;Bessa et al 2009). Pathway analysis confirmed the enrichment of neuroplasticity pathways in MDD, with the involvement of CREB signalling in neurons, synaptic long-term potentiation and axonal guidance signalling (Jia et al 2011;Hunter et al 2013). Interestingly, several members of the integrin signalling pathway, including ITGB3, ZYX, ARF1, CAPNS1, CDC42, ILK, LIMS1, RAC2 and TTN were found differentially expressed between antidepressant responders and nonresponders.…”

Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry

“…This study reported three SNPs rs6966038 in the UBE3C gene ) that showed suggestive association with treatment response and remission [38]. A similar GWAS on the patterns of treatment response using the STAR*D subjects having sustained (n = 869) versus unsustained (n = 247) patterns and a replication attempt at the Genome-Based Therapeutic Drugs for Depression (GENDEP, n = 585) found that the strongest suggestive association was detected at rs10492002 (p = 4.5 × 10 −6 ) in the ACSS3 gene [58]. A GWAS on susceptibility to antidepressant side effects on STAR*D (n = 1439) identified ten linked SNPs in SACM1L gene (p = 4.98 × 10…”

Circulating cytotoxic T cells and natural killer cells as potential predictors for antidepressant response in melancholic depression. Restoration of T regulatory cell populations after antidepressant therapy

“…Therefore, an urgent need exists to identify clinically applicable predictors of treatment response. Prediction tools studied previously include clinical parameters (Fava et al 2008), functional neuroimaging (Furey et al 2013;Samson et al 2011), quantitative electroencephalography ), (pharmaco)genetics (Benedetti et al 2012;Binder et al 2010;Brouwer et al 2006;Hunter et al 2013;McMahon et al 2006;Tansey et al 2012), and gene expression profiling ).…”