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

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.

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.

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%.

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.