CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests a role in male anxiety and ethanol intake.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
19
03
2019
accepted:
27
02
2020
revised:
20
02
2020
pubmed:
24
3
2020
medline:
12
10
2021
entrez:
24
3
2020
Statut:
ppublish
Résumé
Excessive alcohol intake is associated with 5.9% of global deaths. However, this figure is especially acute in men such that 7.6% of deaths can be attributed to alcohol intake. Previous studies identified a significant interaction between genotypes of the galanin (GAL) gene with anxiety and alcohol abuse in different male populations but were unable to define a mechanism. To address these issues the current study analysed the human UK Biobank cohort and identified a significant interaction (n = 115,865; p = 0.0007) between allelic variation (GG or CA genotypes) in the highly conserved human GAL5.1 enhancer, alcohol intake (AUDIT questionnaire scores) and anxiety in men. Critically, disruption of GAL5.1 in mice using CRISPR genome editing significantly reduced GAL expression in the amygdala and hypothalamus whilst producing a corresponding reduction in ethanol intake in KO mice. Intriguingly, we also found the evidence of reduced anxiety-like behaviour in male GAL5.1KO animals mirroring that seen in humans from our UK Biobank studies. Using bioinformatic analysis and co-transfection studies we further identified the EGR1 transcription factor, that is co-expressed with GAL in amygdala and hypothalamus, as being important in the protein kinase C (PKC) supported activity of the GG genotype of GAL5.1 but less so in the CA genotype. Our unique study uses a novel combination of human association analysis, CRISPR genome editing in mice, animal behavioural analysis and cell culture studies to identify a highly conserved regulatory mechanism linking anxiety and alcohol intake that might contribute to increased susceptibility to anxiety and alcohol abuse in men.
Identifiants
pubmed: 32203157
doi: 10.1038/s41380-020-0707-7
pii: 10.1038/s41380-020-0707-7
doi:
Substances chimiques
Ethanol
3K9958V90M
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2263-2276Subventions
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : Wellcome Trust (Wellcome)
ID : 104036/Z/14/Z
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/N017544/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Informations de copyright
© 2020. The Author(s), under exclusive licence to Springer Nature Limited.
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