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Association of intestinal anti-inflammatory drug target genes with psychiatric Disorders: A Mendelian randomization

Guorui Zhao1, Zhe Lu1, Yundan Liao1

  • 1Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China.

Journal of Advanced Research
|May 12, 2024
PubMed
Abstract

Insights

Intestinal anti-inflammatory drug targets, like TPMT and ACAT1, show causal links to bipolar disorder and obsessive-compulsive disorder. Gut microbiota may mediate these effects, offering new therapeutic avenues for psychiatric disorders.

Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Psychiatric disorders pose a significant global health challenge with limited treatment options.
  • The gut-brain axis links inflammatory bowel diseases and psychiatric disorders, suggesting shared biological pathways.
  • The role of intestinal anti-inflammatory drugs in psychiatric conditions remains largely unexplored.

Purpose of the Study:

  • To investigate the causal relationship between intestinal anti-inflammatory drug targets and psychiatric disorders.
  • To explore the potential mediating role of gut microbiota in these associations.
  • To identify novel therapeutic targets for psychiatric conditions.

Main Methods:

  • Two-sample Mendelian randomization (MR) was employed using eQTL and pQTL data from brain, sigmoid colon, and whole blood.
  • Genome-wide association study (GWAS) data for six psychiatric disorders were analyzed.
  • Colocalization analysis and gut microbiota abundance data were used to strengthen evidence and explore mediation.

Main Results:

  • A causal effect of TPMT expression in the amygdala on bipolar disorder risk was identified (OR=1.08, P=4.29×10⁻⁴).
  • This association was mediated by a decrease in Roseburia gut bacteria abundance (10.05%).
  • Elevated ACAT1 expression was causally linked to increased obsessive-compulsive disorder risk (OR=1.62, P=3.64×10⁻⁴).

Conclusions:

  • TPMT and ACAT1 represent novel therapeutic targets for psychiatric disorders.
  • Repurposing existing anti-inflammatory drugs like olsalazine may be a viable treatment strategy.
  • The gut microbiota plays a significant role in the gut-brain axis and psychiatric conditions.
Keywords:
Anti-inflammatoryDrug target geneGut microbiotaGut-brain axisMendelian RandomizationPsychiatric disorder

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