Background: Genetic variations associated with major depressive disorder (MDD) may affect the structural aspects of neural networks mediated by the molecular pathways involved in neuronal survival and synaptic plasticity. However, few studies have applied a novel approach such as whole-exome sequencing (WES) analysis to investigate the genetic contribution to the neurostructural changes in MDD.
Methods: In the first part of the study, we investigated rare variants of selected genes from previous WES studies using a WES analysis in 184 patients with MDD and 82 healthy controls. In the second part of the study, we explored the association between the common genetic variants from the WES analysis and cortical thickness in 91 patients with MDD and 75 healthy controls. The gray-matter thickness of each cortical region was measured using FreeSurfer.
Results: We identified recurrent non-silent variants in 24 MDD-related genes including FASN, MYH13, UNC13D, LILRA1, CACNA1B, TRIO, HOMER3, and BCAR3, and observed eleven recurrently altered copy number alternations where a gain on 15q11.2 and losses on 7q34 and 15q11.1-q11.2 in MDD genomes. We also found that rs11592462 in CDH23, a calcium-dependent cell-adhesion molecule encoding gene, was significantly associated with thinning in the right anterior cingulate cortex.
Limitation: The small sample size may lead our findings to be underpowered regarding rare variants.
Conclusion: The present study identified that non-synonymous rare variants were significantly associated with risk of MDD and found that genetic contributions to the development of MDD may be mediated by alterations in cortical thickness of emotion-processing neural circuits.
Keywords: Anterior cingulate cortex; CDH23; Cortical thickness; Major depressive disorder; Whole-exome sequencing.
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