Aman, A., Slob, E. A.W., Ward, J. , Cullen, B. , Graham, N., Lyall, D. M. , Sattar, N. and Strawbridge, R. J. (2022) Investigating the potential impact of PCSK9-inhibitors on mood disorders using eQTL-based Mendelian randomization. PLoS ONE, 17(12), e0279381. (doi: 10.1371/journal.pone.0279381) (PMID:36580462) (PMCID:PMC9799310)
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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Ward, Dr Joey and Cullen, Dr Breda and Aman, Ms Alisha and Sattar, Professor Naveed and Strawbridge, Dr Rona and Lyall, Dr Donald and Graham, Dr Nicholas |
| Creator Roles: | Aman, A.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review and editing Ward, J.Methodology, Supervision, Writing – review and editing Cullen, B.Writing – review and editing Graham, N.Investigation, Writing – review and editing Lyall, D. M.Methodology, Writing – review and editing Sattar, N.Methodology, Supervision, Writing – review and editing Strawbridge, R. J.Conceptualization, Formal analysis, Methodology, Supervision, Validation, Writing – original draft, Writing – review and editing |
| Authors: | Aman, A., Slob, E. A.W., Ward, J., Cullen, B., Graham, N., Lyall, D. M., Sattar, N., and Strawbridge, R. J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health |
| Journal Name: | PLoS ONE |
| Publisher: | Public Library of Science |
| ISSN: | 1932-6203 |
| ISSN (Online): | 1932-6203 |
| Copyright Holders: | Copyright © 2022 Aman et al. |
| First Published: | First published in PLoS ONE 17(12): e0279381 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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