Rare Functional Variants Associated with Antidepressant Remission in Mexican-Americans: Short title: Antidepressant remission and pharmacogenetics in Mexican-Americans

Abstract

Introduction: Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response.

Method: Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes.

Results: The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR <0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycleprocess.

Limitations: Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate. Our study is based on a small sample size of only 65 Mexican-American individuals. Further studies using larger cohorts are warranted.

Conclusion: Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response.

Trial registration: ClinicalTrials.gov NCT00265291.

Keywords: Antidepressants; Depression; Drug response; Hispanic; Pharmacogenomics; Whole-exome genotyping.

Conflict of interest statement

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Copyright © 2020. Published by Elsevier B.V.

Figures

Figure 1.. The process used to filter out SNP exomic variants genotyped with the Illumina® HumanExome BeadChip-12v1_A to evaluate the role of rare functional variants in the pharmacogenetics of antidepressant response as remitters (n = 36) and non-responders (n = 29).

SNPs were discarded because they were either monoallelic, had more than two alleles, had a call rate lower than 90%, or their genotype proportions deviated from the expected ones as defined by the Hardy-Weinberg equilibrium theorem, with P-values < 0.05/m (m is the number of markers included in the analyses), in both cases and controls. Common variants (allelic frequency of the minor allele higher than 0.01), non-exonic, non-functional variants, and tolerated and conserved variants were theoretically defined by the use of SIFT, PolyPhen2, MutationTaster, Gerp++ and phyloP. The remaining 12,718 variants were used in the rare variant analysis.

Figure 2.. Enriched gene ontology (GO) processes.

Genes significantly associated with remission were analyzed using the ConsensusPathDB engine. Enriched GO processes with P≤0.05 are shown.