PCSK9 Inhibitors and Bipolar Disorder: A Drug Target Mendelian Randomization Study

Objective: Bipolar disorder (BD) patients remain symptomatic. As lipid-lowering drug targets have been linked to BD risk, we used Mendelian randomization (MR) to assess their therapeutic potential. Methods: We conducted MR analyses utilizing genetic variants associated with lipid traits and variants in genes encoding the protein targets of various classes of lipid-lowering drugs. The specific drug classes investigated included 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-Like 1 (NPC1L1). To determine the effects on BD risk, we meta-analyzed MR estimates for regional variants using data from 2 large sample sets. The genetic variants were weighted based on their associations with low-density LDL-c. For lipid-modifying drug targets that exhibited suggestive significance, we further used eQTL data. In addition, we performed colocalization analysis to assess genetic confounding. Results: Genetically proxied inhibition of PCSK9 was strongly associated with a lower risk of developing BD (IVW MR OR=0.82, 95% CI=0.74-0.91, P =2.12e-04, SD reduction in LDL-c) in PGC data set, and in UK Biobank data set ( P =0.03). Sensitivity analyses yielded no statistically significant evidence of bias arising from pleiotropy or genetic confounding. The posterior probability for a common causal variant between PCSK9 inhibition and BD risk was 80.8%. Conclusions: It was observed that PCSK9 showed significant associations with BD risk. These findings indicate that PCSK9 inhibitors have the potential to serve for the treatment of BD.