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Phosphodiesterase and psychiatric disorders: a two-sample Mendelian randomization study.

Miaomiao Jiang1, Weiheng Yan2, Yuyanan Zhang1

  • 1National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China.

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Summary

This study used Mendelian randomization to investigate causal links between phosphodiesterases (PDEs) and psychiatric disorders. Cyclic nucleotide PDEs, particularly those specific to cAMP, show potential causal associations with conditions like schizophrenia and major depressive disorder.

Keywords:
Mendelian randomization studyPhosphodiesterasePsychiatric disorderscAMPcGMP

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Area of Science:

  • Neuroscience
  • Genetics
  • Psychiatry

Background:

  • Observational studies suggest links between phosphodiesterases (PDEs) and psychiatric disorders.
  • Causality of these associations has remained unestablished.
  • PDEs play crucial roles in cyclic nucleotide signaling pathways.

Purpose of the Study:

  • To investigate the potential causal relationships between various cyclic nucleotide phosphodiesterases (PDEs) and nine psychiatric disorders.
  • To differentiate the roles of PDEs that hydrolyze cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), or both.

Main Methods:

  • Utilized a bidirectional two-sample Mendelian randomization (MR) analysis.
  • Employed genome-wide association study (GWAS) data for PDEs and psychiatric disorders.
  • Applied multiple statistical methods including inverse-variance-weighted (IVW), MR-Egger, and weighted median for causal effect estimation.
  • Conducted comprehensive sensitivity analyses to ensure robustness of findings.

Main Results:

  • PDEs specific to cAMP, such as PDE4D and PDE7A, were associated with increased odds of psychiatric disorders including schizophrenia, major depressive disorder, and attention-deficit/hyperactivity disorder.
  • PDEs that hydrolyze both cAMP and cGMP (PDE1A, PDE2A, PDE3A) also showed associations with disorders like autism spectrum disorder, Tourette syndrome, and major depressive disorder.
  • Bidirectional analysis revealed potential causal effects of psychiatric disorders on certain PDE levels, such as obsessive-compulsive disorder influencing PDE6D, PDE2A, and PDE4D.

Conclusions:

  • Established potential causal relationships between specific phosphodiesterases (PDEs) and psychiatric disorders.
  • Findings highlight the role of cAMP-specific PDEs in psychiatric conditions.
  • Suggests that targeted therapies focusing on PDE subtypes may offer promising therapeutic strategies for psychiatric disorders.