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. 2024 Sep 26;19(9):e0310396.
doi: 10.1371/journal.pone.0310396. eCollection 2024.

Investigating the association of the effect of genetically proxied PCSK9i with mood disorders using cis-pQTLs: A drug-target Mendelian randomization study

Alisha Aman  1   2 , Eric A W Slob  3   4   5 , Joey Ward  2 , Naveed Sattar  6 , Rona J Strawbridge  2   7
Affiliations

Investigating the association of the effect of genetically proxied PCSK9i with mood disorders using cis-pQTLs: A drug-target Mendelian randomization study

Alisha Aman et al. PLoS One. .

Abstract

PCSK9-inhibitors (PCSK9i) are new drugs recently approved to lower LDL-cholesterol levels. However, due to the lack of long-term clinical data, the potential adverse effects of long-term use are still unknown. The PCSK9 genetic locus has been recently implicated in mood disorders and hence we wanted to assess if the effect of PCSK9i that block the PCSK9 protein can lead to an increase in the incidence of mood disorders. We used genetically-reduced PCSK9 protein levels (pQTLs) in plasma, serum, cerebrospinal fluid as a proxy for the effect of PCSK9i. We performed Mendelian randomization analyses using PCSK9 levels as exposure and mood disorder traits major depressive disorder, mood instability, and neuroticism score as outcomes. We find no association of PCSK9 levels with mood disorder traits in serum, plasma, and cerebrospinal fluid. We can conclude that genetically proxied on-target effect of pharmacological PCSK9 inhibition is unlikely to contribute to mood disorders.

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Conflict of interest statement

Naveed Sattar reports consulting and/or speaker fees from Abbott Laboratories, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and grant support paid to his institution from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. All other authors declare no potential conflicts. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Association of reduced PCSK9 protein levels in the plasma and serum with mood disorder traits with stringent p-value threshold.
SMR multi-SNP analyses was performed using cis-pQTLs as instruments to assess association of PCSK9 levels (exposure) with mood disorder traits (MDD, mood instability, and neuroticism score) as outcomes. On the X-axis are the outcomes (mood disorder traits and LDL-C as a positive control). The Y-axis depicts the -log10(p-value) for the SMR associations using multiple SNP. Three datasets were used for PCSK9 protein levels: ARIC (plasma), AGES (serum), and PCSK9 meta-GWAS (serum and plasma combined). The direction of the arrow represents the direction of effect with respect to reduction of PCSK9 levels–triangle pointing up: reduction of PCSK9 levels increases the outcome levels/risk, triangle pointing down: reduction of PCSK9 levels reduces the outcome levels/risk. The red line signifies the Bonferroni corrected p-value threshold of 0.0031.
Fig 2
Fig 2. Association of reduced PCSK9 protein levels in the CSF with mood disorder traits.
SMR multi-SNP analyses was performed using cis-pQTLs as instruments to assess association of PCSK9 levels (exposure) with mood disorder traits MDD, and mood instability as outcomes. The x-axis represents the three mood disorder traits and LDL-C as positive control. The y-axis depicts the -log10(p-value) for the SMR associations using multiple SNP. The shape represents the direction of effect with respect to reduction of PCSK9 levels: triangle pointing up: reduction of PCSK9 levels increases the outcome levels/risk, triangle pointing down: reduction of PCSK9 levels reduces the outcome levels/risk. Red line signifies the Bonferroni corrected p-value threshold of 0.0031.
See this image and copyright information in PMC

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