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Rare Functional Variants Associated with Antidepressant Remission in Mexican-Americans: Short title: Antidepressant
Ma-Li Wong1, Mauricio Arcos-Burgos2, Sha Liu3
1Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, USA; Department of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY, USA; Mind & Brain Theme, South Australian Health and Medical Research Institute Adelaide, South Australia, Australia; Department of Psychiatry, Flinders University College of Medicine and Public Health, Bedford Park, South Australia, Australia.
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.
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