Genome-wide copy number variation-, validation- and screening study implicates a novel copy number polymorphism associated with suicide attempts in major depressive disorder

Background: The genetic basis of suicide attempts (SA) remained unclear, especially for the copy number variations (CNVs) involved. The present study aimed to identify the susceptibility variants associated with SA among major depressive disorder (MDD) patients in Chinese, covering both single-nucleotide polymorphisms and CNVs. Methods: We conducted GWAS on MDD patients with or without SA and top results were tested in a replication study. A genome-wide CNV study was performed. Subsequently, a validation assay using the qRT-PCR technology was performed to confirm the existence of the associated CNV and then applied to the entire cohort to examine the association. Results: In CNV analysis, we found that the global rate of CNV was higher in SA compared to non-SA subjects (p=0.023). The genome-wide CNV study revealed a SA-associated CNV region that achieved genome-wide significance (corrected p-value=0.014). The associated CNV was successfully validated and identified to be a common variant in this cohort and its deletion rate was higher in suicide attempters (OR=2.05). Based on the GTEx database, genetic variants that probe this CNV was significantly associated with the expression level of ZNF33B in two brain regions (p-value<4.2e-05). Besides, there was a significant interaction between neuroticism and the CNV in affecting suicidal risk; the CNV showed a significant effect (OR=2.58) in subjects with high neuroticism only. Conclusions: We identified a new common CNV that may be involved in the etiology of SA. These findings imply an important role of common CNVs in the etiology of SA, which suggests a new promising avenue for investigating the genetic architecture of SA.