全基因组拷贝数变异、验证和筛查研究提示一种新的拷贝数多态性与重度抑郁症自杀未遂有关。
Genome-wide copy number variation-, validation- and screening study implicates a new copy number polymorphism associated with suicide attempts in major depressive disorder.
机构信息
The Nethersole School of Nursing, The Croucher Laboratory for Human Genomics, China; Department of Psychiatry, N.T, Hong Kong Special Administrative Region; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, N.T, Hong Kong Special Administrative Region.
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, N.T, Hong Kong Special Administrative Region.
出版信息
Gene. 2020 Sep 10;755:144901. doi: 10.1016/j.gene.2020.144901. Epub 2020 Jun 15.
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.
背景
自杀未遂（SA）的遗传基础仍不清楚。特别是拷贝数变异（CNVs）的作用仍有待阐明。本研究旨在确定与中国重度抑郁症（MDD）患者 SA 相关的易感性变异，包括 CNVs 和单核苷酸多态性（SNPs）。
方法
我们对有和无 SA 的 MDD 患者进行了全基因组关联研究（GWAS），并在复制研究中对顶级结果进行了测试。还进行了全基因组 CNV 研究。随后，使用 qRT-PCR 技术进行验证试验以确认任何相关的 CNVs，然后将其应用于整个队列以检查关联。
结果
尽管 GWAS 未发现任何达到全基因组显著水平的 SNPs，但我们在基因分析中确定 TPH2 为顶级易感基因（p 值= 2.75e-05），这是其在 5-羟色胺能系统中的作用的强有力的生物学候选基因。至于 CNV 分析，我们发现 SA 组的 CNV 总发生率高于非 SA 组（p 值= 0.023）。全基因组 CNV 研究发现一个与 SA 相关的 CNV 区域达到全基因组显著水平（校正 p 值= 0.014）。通过更严格的 qRT-PCR 试验成功验证了相关的 CNV，并确定其在本队列中为常见变异。其缺失率在 SA 患者中更高[OR=2.05（1.02-4.12），调整 p 值=0.045]。基于 GTEx 数据库，探测该 CNV 的遗传变异与两个脑区的 ZNF33B 表达水平显著相关（p 值<4.2e-05）。在分层分析中，CNV 在神经质较高的患者中显示出显著的效果[OR=2.58（1.06-6.27），p 值=0.039]，但在神经质中等或较低的患者中没有显示出显著效果。
结论
我们发现了一种可能与 SA 病因有关的新的常见 CNV。这一发现揭示了常见 CNVs 在 SA 病理生理学中的重要作用，为研究其遗传结构提供了一个新的有前途的途径。
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