Investigating the potential impact of PCSK9-inhibitors on mood disorders using eQTL-based Mendelian randomization

Abstract

Prescription of PCSK9-inhibitors has increased in recent years but not much is known about its off-target effects. PCSK9-expression is evident in non-hepatic tissues, notably the brain, and genetic variation in the PCSK9 locus has recently been shown to be associated with mood disorder-related traits. We investigated whether PCSK9 inhibition, proxied by a genetic reduction in expression of PCSK9 mRNA, might have a causal adverse effect on mood disorder-related traits. We used genetic variants in the PCSK9 locus associated with reduced PCSK9 expression (eQTLs) in the European population from GTEx v8 and examined the effect on PCSK9 protein levels and three mood disorder-related traits (major depressive disorder, mood instability, and neuroticism), using summary statistics from the largest European ancestry genome-wide association studies. We conducted summary-based Mendelian randomization analyses to estimate the causal effects, and attempted replication using data from eQTLGen, Brain-eMETA, and the CAGE consortium. We found that genetically reduced PCSK9 gene-expression levels were significantly associated with reduced PCSK9 protein levels but not with increased risk of mood disorder-related traits. Further investigation of nearby genes demonstrated that reduced USP24 gene-expression levels was significantly associated with increased risk of mood instability (p-value range = 5.2x10-5-0.03), and neuroticism score (p-value range = 2.9x10-5-0.02), but not with PCSK9 protein levels. Our results suggest that genetic variation in this region acts on mood disorders through a PCSK9-independent pathway, and therefore PCSK9-inhibitors are unlikely to have an adverse impact on mood disorder-related traits.

Fig 1. MR association of PCSK9 and USP24 gene-expression levels with phenotypes of interest.

The Y-axis represents the -log₁₀ p-value of the MR association, while the direction signifies the direction of effect of gene-expression reduction, which serves as a proxy for PCSK9i. SMR multi-SNP analyses association of the available 25 tissues for PCSK9 and USP24 gene-expression in GTEx v8 for outcomes Mood swings (A) and Neuroticism score (B). (C) MR (IVW) for PCSK9 and USP24 gene-expression with combined eQTL estimates from all available tissues in GTEx v8. The blue and red lines signify p-value of 0.05 and Bonferroni-corrected threshold for 5 traits per gene of 0.005, respectively.

Fig 2. Cross-tissue MR association of PCSK9 and USP24 gene-expression levels with phenotypes of interest.

The Y-axis represents the -log₁₀ p-value of the MR association, while the direction signifies the direction of effect of gene-expression reduction, which serves as a proxy for PCSK9i. MR (IVW) for PCSK9 and USP24 gene-expression with combined eQTL estimates from all available tissues in GTEx v8. The blue and red lines signify p-value of 0.05 and Bonferroni-corrected threshold for 5 traits per gene of 0.005, respectively.

Fig 3. MR association of USP24 gene-expression levels with phenotypes of interest in replication cohorts.

The y-axis represents the -log₁₀ p-value of the MR association, while the direction signifies the direction of effect of gene-expression reduction, which serves as a proxy to the corresponding drug effect. SMR multi-SNP analyses associations for CAGE consortium (peripheral blood), eQTLGen consortium (whole blood), and Brain-eMETA dataset (brain) for USP24 gene-expression. The blue and red lines signify p-value of 0.05 and Bonferroni-corrected threshold for 5 traits per gene of 0.005.