Association of adenosine triphosphate-related genes to major depression and suicidal behavior: Cognition as a potential mediator

• Published in: Journal of affective disorders Vol. 323; pp. 131 - 139
• Main Authors: Zheng, Shuqiong, Guo, Jia, Xin, Qianqian, Galfalvy, Hanga, Ye, Youran, Yan, Na, Qian, Rongrong, Mann, J. John, Li, Enze, Xue, Xiang, Yin, Honglei
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.02.2023
• Subjects: Cognition; Depression; Depressive Disorder, Major - psychology; Gene polymorphism; Haplotype; Humans; Polymorphism, Single Nucleotide; Psychiatric/Mental Health; RNA, Messenger - genetics; RNA, Messenger - metabolism; Suicidal Ideation; Suicide attempt; ACC; RT; AD; PUFA; ANT; DNS; Depression; Cognition; eQTL; MDD; Gene polymorphism; HV; mQTL; Suicide attempt; DSA; EET; SST; sEH; HAMD-24; SNPs; GABA; Haplotype; C-SSRS; PCR; Hamilton Depression Scale-24 items; Columbia-Suicide Severity Rating Scale; accuracy; soluble epoxide hydrolase; epoxyeicosatrienoic acid; single nucleotide polymorphisms; Alzheimer's disease; depressed non-suicide attempters; Attention Network Test; depressed suicide attempters; healthy volunteers; real-time polymerase chain reaction; Suicide Stroop task, SST; gamma-aminobutyric acid; methylation quantitative trait locus; expression quantitative trait locus; major depressive disorder; response time; polyunsaturated fatty acid
• ISSN: 0165-0327; 1573-2517; 1573-2517
• DOI: 10.1016/j.jad.2022.11.042

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. •Cognitive function may be the mediator between SNP rs9331949 and MDD.•Multiple levels of evidence indicated the relationship between P2X2 and depression.•Haplotype-based evidence showed an association between EPHX2 and suicide.