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Investigating the potential impact of PCSK9-inhibitors on mood disorders using eQTL-based Mendelian randomization
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 trait...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9799310/ https://www.ncbi.nlm.nih.gov/pubmed/36580462 http://dx.doi.org/10.1371/journal.pone.0279381 |
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author | Aman, Alisha Slob, Eric A. W. Ward, Joey Cullen, Breda Graham, Nicholas Lyall, Donald M. Sattar, Naveed Strawbridge, Rona J. |
author_facet | Aman, Alisha Slob, Eric A. W. Ward, Joey Cullen, Breda Graham, Nicholas Lyall, Donald M. Sattar, Naveed Strawbridge, Rona J. |
author_sort | Aman, Alisha |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9799310 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-97993102022-12-30 Investigating the potential impact of PCSK9-inhibitors on mood disorders using eQTL-based Mendelian randomization Aman, Alisha Slob, Eric A. W. Ward, Joey Cullen, Breda Graham, Nicholas Lyall, Donald M. Sattar, Naveed Strawbridge, Rona J. PLoS One Research Article 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. Public Library of Science 2022-12-29 /pmc/articles/PMC9799310/ /pubmed/36580462 http://dx.doi.org/10.1371/journal.pone.0279381 Text en © 2022 Aman et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Aman, Alisha Slob, Eric A. W. Ward, Joey Cullen, Breda Graham, Nicholas Lyall, Donald M. Sattar, Naveed Strawbridge, Rona J. Investigating the potential impact of PCSK9-inhibitors on mood disorders using eQTL-based Mendelian randomization |
title | Investigating the potential impact of PCSK9-inhibitors on mood disorders using eQTL-based Mendelian randomization |
title_full | Investigating the potential impact of PCSK9-inhibitors on mood disorders using eQTL-based Mendelian randomization |
title_fullStr | Investigating the potential impact of PCSK9-inhibitors on mood disorders using eQTL-based Mendelian randomization |
title_full_unstemmed | Investigating the potential impact of PCSK9-inhibitors on mood disorders using eQTL-based Mendelian randomization |
title_short | Investigating the potential impact of PCSK9-inhibitors on mood disorders using eQTL-based Mendelian randomization |
title_sort | investigating the potential impact of pcsk9-inhibitors on mood disorders using eqtl-based mendelian randomization |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9799310/ https://www.ncbi.nlm.nih.gov/pubmed/36580462 http://dx.doi.org/10.1371/journal.pone.0279381 |
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