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Causal effects of lipid-lowering drug targets on psychiatric disorders: A drug-target Mendelian randomization study

Yan Wang1, Xin Liu2, Shuo Huang2

  • 1Fengqiu County Traditional Chinese Medicine Hospital, China.

The Journal of International Medical Research
|January 31, 2026
PubMed

Insights

Lipid-lowering drug targets show distinct impacts on mental health. HMGCR and PCSK9 inhibition may increase major depressive disorder risk, while NPC1L1 inhibition may decrease it.

Area of Science:

  • Pharmacogenomics
  • Psychiatric Genetics
  • Cardiovascular Pharmacology

Background:

  • The pleiotropic effects of lipid-lowering therapies on mental health are not fully understood.
  • Major lipid-lowering drug targets include HMGCR, NPC1L1, and PCSK9.
  • Understanding these effects is crucial due to the widespread use of these therapies, especially in aging populations.

Purpose of the Study:

  • To investigate the causal impact of genetically proxied inhibition of HMGCR, NPC1L1, and PCSK9 on psychiatric disorders.
  • To utilize a drug-target Mendelian randomization approach for robust causal inference.
  • To assess the effects on anorexia nervosa, anxiety, bipolar disorder, major depressive disorder, neuroticism, obsessive compulsive disorder, and schizophrenia.

Main Methods:

  • Employed a Mendelian randomization approach using genetic variants near HMGCR, NPC1L1, and PCSK9 genes.
  • Utilized summary-level data from large-scale genome-wide association studies for seven psychiatric outcomes.
  • Applied the inverse-variance weighted method as the primary analysis, with multiple sensitivity analyses for robustness.

Main Results:

  • Genetically proxied HMGCR inhibition was linked to an increased risk of major depressive disorder (OR=1.16).
  • NPC1L1 inhibition showed an association with a decreased risk of major depressive disorder (OR=0.88).
  • PCSK9 inhibition was associated with increased risks of major depressive disorder (OR=1.16) and bipolar disorder (OR=1.28).

Conclusions:

  • Genetic evidence suggests distinct effects of lipid-lowering drug targets on psychiatric disorders.
  • Findings underscore the need for further clinical and mechanistic research into these associations.
  • These insights are particularly relevant for aging populations using lipid-lowering therapies.

Keywords:
Mendelian randomizationezetimibeproprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitorspsychiatric disordersstatins

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