In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 12 ( 2022-12-29), p. e0279381-
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.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0279381
DOI:
10.1371/journal.pone.0279381.g001
DOI:
10.1371/journal.pone.0279381.g002
DOI:
10.1371/journal.pone.0279381.g003
DOI:
10.1371/journal.pone.0279381.s001
DOI:
10.1371/journal.pone.0279381.s002
DOI:
10.1371/journal.pone.0279381.s003
DOI:
10.1371/journal.pone.0279381.s004
DOI:
10.1371/journal.pone.0279381.s005
DOI:
10.1371/journal.pone.0279381.s006
DOI:
10.1371/journal.pone.0279381.s007
DOI:
10.1371/journal.pone.0279381.s008
DOI:
10.1371/journal.pone.0279381.s009
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2267670-3
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