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

Abstract

Background: The genetic basis of suicide attempts (SA) remains unclear. Especially the role of copy number variations (CNVs) remains to be elucidated. The present study aimed to identify susceptibility variants associated with SA among Chinese with major depressive disorder (MDD), covering both CNVs and single-nucleotide polymorphisms (SNPs).

Methods: We conducted a genome-wide association study (GWAS) on MDD patients with and without SA and top results were tested in a replication study. A genome-wide CNV study was also performed. Subsequently, a validation assay using qRT-PCR technology was performed to confirm any associated CNVs and then applied to the entire cohort to examine the association.

Results: Although GWAS did not identify any SNPs reaching genome-wide significance, we identified TPH2 as the top susceptibility gene (p-value = 2.75e-05) in gene-based analysis, which is a strong biological candidate for its role in the serotonergic system. As for CNV analysis, we found that the global rate of CNV was higher in SA than that in non-SA subjects (p-value = 0.023). Genome-wide CNV study revealed an SA-associated CNV region that achieved genome-wide significance (corrected p-value = 0.014). The associated CNV was successfully validated with a more rigorous qRT-PCR assay and identified to be a common variant in this cohort. Its deletion rate was higher in SA subjects [OR = 2.05 (1.02-4.12), adjusted p-value = 0.045]. Based on the GTEx database, genetic variants that probed this CNV were significantly associated with the expression level of ZNF33B in two brain regions (p-value < 4.2e-05). In stratified analysis, the CNV showed a significant effect [OR = 2.58 (1.06-6.27), p-value = 0.039] in those with high neuroticism but not in those with average or low neuroticism.

Conclusions: We identified a new common CNV likely involved in the etiology of SA. This finding sheds light on an important role of common CNVs in the pathophysiology of SA, suggesting a new promising avenue for investigating its genetic architecture.

Keywords: GWAS; Genome-wide copy number variation study; Suicide attempts; qRT-PCR assay.