Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests a role in male anxiety and ethanol intake

Andrew R. McEwan, Connor Davidson, Elizabeth Hay, Yvonne Turnbull, Johanna Celene Erickson, Pietro Marini, Dana Wilson, Andrew M. McIntosh, Mark J. Adams, Chris Murgatroyd, Perry Barrett, Mirela Delibegovic, Toni-Kim Clarke, Alasdair MacKenzie
doi: https://doi.org/10.1101/572065
Andrew R. McEwan
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, Scotland, UK, AB25 2ZD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Connor Davidson
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, Scotland, UK, AB25 2ZD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elizabeth Hay
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, Scotland, UK, AB25 2ZD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yvonne Turnbull
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, Scotland, UK, AB25 2ZD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Johanna Celene Erickson
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, Scotland, UK, AB25 2ZD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pietro Marini
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, Scotland, UK, AB25 2ZD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dana Wilson
4Rowett Institute of Nutrition and Health, School of Medicine, Medical Sciences and Nutrition, Foresterhill, University of Aberdeen, Aberdeen, Scotland, UK, AB25 2ZD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew M. McIntosh
3Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Scotland, UK, EH8 9YL
5Division of Psychiatry, University of Edinburgh, Scotland, UK, EH8 9YL
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark J. Adams
5Division of Psychiatry, University of Edinburgh, Scotland, UK, EH8 9YL
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chris Murgatroyd
2E202, School of Healthcare Sciences, John Dalton Building, Manchester Campus, Manchester Metropolitan University, Manchester UK. M15 6BH
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Perry Barrett
4Rowett Institute of Nutrition and Health, School of Medicine, Medical Sciences and Nutrition, Foresterhill, University of Aberdeen, Aberdeen, Scotland, UK, AB25 2ZD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mirela Delibegovic
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, Scotland, UK, AB25 2ZD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Toni-Kim Clarke
5Division of Psychiatry, University of Edinburgh, Scotland, UK, EH8 9YL
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alasdair MacKenzie
1School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, Scotland, UK, AB25 2ZD
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: mbi167@abdn.ac.uk
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

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 that was consistent with these previous studies. 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 evidence of reduced anxiety-like behaviour in male GAL5.1KO animals mirroring that seen in humans. 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.

Footnotes

  • This version of the manuscript contains more conclusive GAL5.1 CRISPR mouse knockout anxiety data as well as more robust PKC data.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted December 13, 2019.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests a role in male anxiety and ethanol intake
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests a role in male anxiety and ethanol intake
Andrew R. McEwan, Connor Davidson, Elizabeth Hay, Yvonne Turnbull, Johanna Celene Erickson, Pietro Marini, Dana Wilson, Andrew M. McIntosh, Mark J. Adams, Chris Murgatroyd, Perry Barrett, Mirela Delibegovic, Toni-Kim Clarke, Alasdair MacKenzie
bioRxiv 572065; doi: https://doi.org/10.1101/572065
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
CRISPR disruption and UK Biobank analysis of a highly conserved polymorphic enhancer suggests a role in male anxiety and ethanol intake
Andrew R. McEwan, Connor Davidson, Elizabeth Hay, Yvonne Turnbull, Johanna Celene Erickson, Pietro Marini, Dana Wilson, Andrew M. McIntosh, Mark J. Adams, Chris Murgatroyd, Perry Barrett, Mirela Delibegovic, Toni-Kim Clarke, Alasdair MacKenzie
bioRxiv 572065; doi: https://doi.org/10.1101/572065

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genetics
Subject Areas
All Articles
  • Animal Behavior and Cognition (3506)
  • Biochemistry (7348)
  • Bioengineering (5324)
  • Bioinformatics (20266)
  • Biophysics (10020)
  • Cancer Biology (7744)
  • Cell Biology (11306)
  • Clinical Trials (138)
  • Developmental Biology (6437)
  • Ecology (9954)
  • Epidemiology (2065)
  • Evolutionary Biology (13325)
  • Genetics (9361)
  • Genomics (12587)
  • Immunology (7702)
  • Microbiology (19027)
  • Molecular Biology (7444)
  • Neuroscience (41049)
  • Paleontology (300)
  • Pathology (1230)
  • Pharmacology and Toxicology (2138)
  • Physiology (3161)
  • Plant Biology (6861)
  • Scientific Communication and Education (1273)
  • Synthetic Biology (1897)
  • Systems Biology (5313)
  • Zoology (1089)