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

Objectives The pleiotropic effects of lipid-lowering therapies on mental health remain incompletely understood. This study aimed to investigate the causal impact of genetically proxied inhibition of three major lipid-lowering drug targets, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), Niemann-Pick C1-like protein 1 (NPC1L1), and proprotein convertase subtilisin/kexin type 9 (PCSK9), on a spectrum of psychiatric disorders using a drug–target Mendelian randomization approach. Methods We used genetic variants located within or near the HMGCR, NPC1L1, and PCSK9 gene regions that are associated with low-density lipoprotein cholesterol levels as proxies for pharmacological inhibition. Summary-level data were obtained from large-scale genome-wide association studies for seven psychiatric outcomes: anorexia nervosa, anxiety, bipolar disorder, major depressive disorder, neuroticism, obsessive compulsive disorder, and schizophrenia. The inverse-variance weighted method was employed as the primary Mendelian randomization approach, supplemented by multiple sensitivity analyses to assess robustness. Results Genetically proxied inhibition of HMGCR was associated with an increased risk of major depressive disorder (odds ratio = 1.16; 95% confidence interval: 1.07–1.25; p = 4.5e−04). In contrast, NPC1L1 inhibition was associated with a decreased risk of major depressive disorder (odds ratio = 0.88; 95% confidence interval: 0.84–0.92; p = 8.1e−08). PCSK9 inhibition was significantly associated with an increased risk of major depressive disorder (odds ratio = 1.16; 95% confidence interval: 1.06–1.26; p = 8.2e−04) and bipolar disorder (odds ratio = 1.28; 95% confidence interval: 1.19–1.38; p = 9.4e−12). No significant associations were observed between these targets and the remaining psychiatric outcomes. Conclusions This study provides genetic evidence that lipid-lowering drug targets exert distinct effects on psychiatric disorders. These findings highlight the importance of further clinical and mechanistic studies, particularly given the widespread use of lipid-lowering therapies in aging populations who are vulnerable to mental health conditions.