Department of Psychiatry, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, China.
Department of Biostatistics, Columbia University, New York, NY, United States.
J Affect Disord. 2023 Feb 15;323:131-139. doi: 10.1016/j.jad.2022.11.042. Epub 2022 Nov 25.
Soluble epoxide hydrolase (sEH, encoded by EPHX2) and P2X2 (a subtype of ATP receptors) may mediate the antidepressant-like effects of ATP. We sought to determine whether polymorphisms and mRNA expression of EPHX2 and P2X2 are associated with depression and suicidal behavior and how cognition may mediate such associations.
We examined 83 single nucleotide polymorphisms (SNPs) of EPHX2 and P2X2. Subjects were MDD suicide attempters (N = 143), MDD non-suicide attempters (N = 248), and healthy volunteers (HV, N = 110). Data on demographics, depression severity, and suicide attempts were collected. Participants completed a set of cognitive tasks. Polymorphisms were genotyped using MALDI-TOF MS within the MassARRAY system. The expression of mRNA was measured using real-time polymerase chain reaction (RT-PCR).
Cognitive function was a significant mediator (p = 0.006) of the genetic effect on depression. Allele C of rs202059124 was associated with depression risk (OR = 11.57, 95%CI: 2.33-209.87, p = 0.0181). A significant relationship was found between P2X2 mRNA expression and depression (OR = 0.68, 95%CI: 0.49-0.94, p = 0.0199). One haploblock (rs9331942 and rs2279590) was associated with suicide attempts: subjects with haplotype GC (frequency = 19.8 %, p = 0.017) and AT (frequency = 35.2 %, p < 0.001) had a lower rate of suicide attempts.
Our results confirmed that cognitive impairment plays a role in the effect of rs9331949 on depression. Moreover, we confirmed a relationship between P2X2, EPHX2, and MDD in humans and presented preliminary haplotype-based evidence that implicates EPHX2 in suicide.
The main limitation of this study is the limited sample size. More comprehensive and multi-domain cognition tasks and different assessment measures are required in further study.
可溶型环氧化物水解酶（sEH，由 EPHX2 编码）和 P2X2（ATP 受体的一种亚型）可能介导 ATP 的抗抑郁样作用。我们试图确定 EPHX2 和 P2X2 的多态性和 mRNA 表达是否与抑郁和自杀行为有关，以及认知功能如何介导这种关联。
我们研究了 EPHX2 和 P2X2 的 83 个单核苷酸多态性（SNP）。研究对象为 MDD 自杀未遂者（N=143）、MDD 非自杀未遂者（N=248）和健康志愿者（HV，N=110）。收集了人口统计学、抑郁严重程度和自杀尝试的数据。参与者完成了一组认知任务。使用基质辅助激光解吸电离飞行时间质谱（MALDI-TOF MS）在 MassARRAY 系统内对 SNP 进行基因分型。使用实时聚合酶链反应（RT-PCR）测量 mRNA 的表达。
认知功能是遗传效应影响抑郁的一个显著中介因素（p=0.006）。rs202059124 的等位基因 C 与抑郁风险相关（OR=11.57，95%CI：2.33-209.87，p=0.0181）。发现 P2X2 mRNA 表达与抑郁之间存在显著关系（OR=0.68，95%CI：0.49-0.94，p=0.0199）。一个单倍型块（rs9331942 和 rs2279590）与自杀尝试有关：具有 GC 单倍型（频率=19.8%，p=0.017）和 AT 单倍型（频率=35.2%，p<0.001）的受试者自杀尝试率较低。
我们的研究结果证实，认知障碍在 rs9331949 对抑郁的影响中起作用。此外，我们在人类中证实了 P2X2、EPHX2 和 MDD 之间的关系，并提供了初步的基于单倍型的证据，表明 EPHX2 与自杀有关。
本研究的主要局限性是样本量有限。在进一步的研究中需要更全面和多领域的认知任务和不同的评估措施。
