Genome-wide association study of antidepressant response: involvement of the inorganic cation transmembrane transporter activity pathway.

Enrico Cocchi,Chi-Un Pae,Prakash S Masand,Soo-Jung Lee,Alessandro Serretti,Chiara Fabbri,Ashwin A Patkar,Changsu Han

doi:10.1186/s12888-016-0813-x

Abstract

BackgroundGenome-wide association studies (GWAS) represent the current frontier in pharmacogenomics. Thousands of subjects of Caucasian ancestry have been included in previous GWAS investigating antidepressant response. GWAS focused on this phenotype are lacking in Asian populations.MethodsA sample of 109 major depressive disorder (MDD) patients of Korean origin in antidepressant treatment was collected. Phenotypes were response and remission according to the Hamilton Rating Scale for Depression (HRSD). Genome-wide genotyping was performed using the Illumina Human Omni2.5-8 platform. The same phenotypes were used in the STAR*D level 1 (n = 1677) for independent replication. In order to corroborate findings and increase the comparability between the two datasets, three levels of analysis (SNPs, genes and pathways) were carried out. Bonferroni correction, permutations, and replication across samples were used to reduce the risk of false positives.ResultsAmong the genes replicated across the two samples (permutated p < 0.05 in both of them), CTNNA3 appeared promising. The inorganic cation transmembrane transporter activity pathway (GO:0022890) was associated with antidepressant response in both samples (p = 2.9e-5 and p = 0.001 in the Korean and STAR*D samples, respectively) and this pathway included CACNA1A, CACNA1C, and CACNB2 genes.ConclusionsThe present study supported the involvement of genes coding for subunits of L-type voltage-gated calcium channel in antidepressant efficacy across different ethnicities but replication of findings is required before any definitive statement.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-016-0813-x) contains supplementary material, which is available to authorized users.

Highlights

Genome-wide association studies (GWAS) represent the current frontier in pharmacogenomics
Less GWAS data are available in regard to antidepressant efficacy in samples of Asian ancestry compared to Caucasian populations and previous studies performed only SNP-level analysis
The present study investigated the genetic markers of antidepressant response/remission in two independent genome-wide datasets through SNP, gene- and pathway-based analyses

Summary

Introduction

Genome-wide association studies (GWAS) represent the current frontier in pharmacogenomics. To the best of our knowledge, only another GWAS investigated antidepressant response in a Korean population and it reported two SNPs in the AUTS2 (Autism Susceptibility Candidate 2) gene (rs7785360 and rs12698828) as genome-wide significant [9]. AUTS2 codes for a nuclear protein that is expressed in the central nervous system in humans, especially in some hippocampal areas and it has been implicated in neurodevelopmental disorders, schizoaffective and bipolar affective disorders [9]. Another recent GWAS included a relevant number of Asian subjects especially from Taiwan and secondly from Japan and it did not report genome-wide significant results. NRG1 (neuregulin-1) is interesting since this gene is involved in many aspects of brain development and it was associated with schizophrenia risk [10]

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Discussion

Conclusion