Citation

Rao S, Shi M, Han X, Ho Bun Lam M, Tong Chien W, Zhou K, Liu G, Kwok Wing Y, So HC, Miu Yee Waye M. Gene 2020; ePub(ePub): ePub.

Affiliation

The Nethersole School of Nursing, The Croucher Laboratory for Human Genomics, China. Electronic address: mary-waye@cuhk.edu.hk.

Copyright

(Copyright © 2020, Elsevier Publishing)

DOI

10.1016/j.gene.2020.144901

PMID

32554045

Abstract

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 Chinese people with major depressive disorder (MDD), covering both CNVs and single-nucleotide polymorphisms.

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 also performed. Subsequently, a validation assay using qRT-PCR technology was performed to confirm any associated CNV 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). 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 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 involving in the etiology of SA. This finding sheds light on an important role of the common CNVs in the understanding of genetic basis of SA, suggesting a new promising avenue for investigating the SA's genetic architecture.

Copyright © 2020. Published by Elsevier B.V.

Language: en

Keywords

GWAS; SA; genome-wide copy number variation study; qRT-PCR assay