背景:在观察性研究中,磷酸二酯酶(PDEs)与精神疾病有关;然而,协会的因果关系仍然不确定。
方法:具体来说,环核苷酸PDE是从全基因组关联研究(GWAS)中收集的,包括通过水解环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)(PDE1A,PDE2A,和PDE3A),特定于cGMP(PDE5A,PDE6D,和PDE9A)和cAMP(PDE4D和PDE7A)。我们进行了双向双样本孟德尔随机化(MR)分析,以研究PDE与9种精神疾病之间的关系。逆方差加权(IVW)方法,MR-Egger,和加权中位数用于估计因果效应。Cochran的Q测试,MR-Egger截距测试,斯泰格MR试验,遗漏分析,漏斗图,和MR多效性残差和异常值(MR-PRESSO)用于敏感性分析。
结果:cAMP特异性PDEs与较高几率的精神疾病相关。例如,PDE4D和精神分裂症(SCZ)(优势比(OR)=1.0531,PIVW=0.0414),以及重度抑郁障碍(MDD)(OR=1.0329,PIVW=0.0011)。同样,PDE7A与注意力缺陷/多动障碍(ADHD)的几率更高(OR=1.0861,PIVW=0.0038)。探索特定的PDE亚型和增加细胞内cAMP水平可以为靶向干预的发展提供信息。我们还观察到PDE(同时水解cAMP和cGMP)与精神疾病有关[对于自闭症谱系障碍,PDE1A的OR为1.0836;对于Tourette综合征(TS),PDE2A的OR为0.8968,对于SCZ,PDE3A的OR为0.9449;对于MDD,PDE3A的OR为0.9796;P<0.05]。此外,精神疾病对PDEs也有一定的因果效应[强迫症对PDE6D升高和PDE2A和PDE4D降低;神经性厌食症对PDE9A降低]。使用多重敏感性分析发现MR结果是稳健的。
结论:在这项研究中,建立了血浆PDE蛋白与精神疾病之间的潜在因果关系.探索本研究中未包含的其他PDE亚型可以更全面地了解PDE在精神疾病中的作用。针对PDE亚型的特定药物的开发可能是治疗精神疾病的有希望的治疗方法。
Phosphodiesterases (PDEs) have been associated with psychiatric disorders in observational studies; however, the causality of associations remains unestablished.
Specifically, cyclic nucleotide PDEs were collected from genome-wide association studies (GWASs), including PDEs obtained by hydrolyzing both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (PDE1A, PDE2A, and PDE3A), specific to cGMP (PDE5A, PDE6D, and PDE9A) and cAMP (PDE4D and PDE7A). We performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the relationship between PDEs and nine psychiatric disorders. The inverse-variance-weighted (IVW) method, MR-Egger, and weighted median were used to estimate causal effects. The Cochran\'s Q test, MR-Egger intercept test, MR Steiger test, leave-one-out analyses, funnel plot, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for sensitivity analyses.
The PDEs specific to cAMP were associated with higher-odds psychiatric disorders. For example, PDE4D and schizophrenia (SCZ) (odds ratios (OR) = 1.0531, PIVW = 0.0414), as well as major depressive disorder (MDD) (OR = 1.0329, PIVW = 0.0011). Similarly, PDE7A was associated with higher odds of attention-deficit/hyperactivity disorder (ADHD) (OR = 1.0861, PIVW = 0.0038). Exploring specific PDE subtypes and increase intracellular cAMP levels can inform the development of targeted interventions. We also observed PDEs (which hydrolyzes both cAMP and cGMP) was associated with psychiatric disorders [OR of PDE1A was 1.0836 for autism spectrum disorder; OR of PDE2A was 0.8968 for Tourette syndrome (TS) and 0.9449 for SCZ; and OR of PDE3A was 0.9796 for MDD; P < 0.05]. Furthermore, psychiatric disorders also had some causal effects on PDEs [obsessive-compulsive disorder on increased PDE6D and decreased PDE2A and PDE4D; anorexia nervosa on decreased PDE9A]. The results of MR were found to be robust using multiple sensitivity analysis.
In this
study, potential causal relationships between plasma PDE proteins and psychiatric disorders were established. Exploring other PDE subtypes not included in this
study could provide a more comprehensive understanding of the role of PDEs in psychiatric disorders. The development of specific medications targeting PDE subtypes may be a promising therapeutic approach for treating psychiatric disorders.