Genome-wide association mapping of ethanol sensitivity in the Diversity Outbred mouse population

Clarissa C Parker; Vivek M Philip; Daniel M Gatti; Steven Kasparek; Andrew M Kreuzman; Lauren Kuffler; Benjamin Mansky; Sophie Masneuf; Kayvon Sharif; Erica Sluys; Dominik Taterra; Walter M Taylor; Mary Thomas; Oksana Polesskaya; Abraham A Palmer; Andrew Holmes; Elissa J Chesler

doi:10.1111/acer.14825

Genome-wide association mapping of ethanol sensitivity in the Diversity Outbred mouse population

Alcohol Clin Exp Res. 2022 Jun;46(6):941-960. doi: 10.1111/acer.14825. Epub 2022 Apr 17.

Authors

Clarissa C Parker¹, Vivek M Philip², Daniel M Gatti², Steven Kasparek¹, Andrew M Kreuzman¹, Lauren Kuffler³, Benjamin Mansky¹, Sophie Masneuf⁴, Kayvon Sharif¹, Erica Sluys⁴, Dominik Taterra¹, Walter M Taylor¹, Mary Thomas¹, Oksana Polesskaya^{5

6}, Abraham A Palmer^{5

6}, Andrew Holmes⁴, Elissa J Chesler³

Affiliations

¹ Department of Psychology and Program in Neuroscience, Middlebury College, Middlebury, Vermont, USA.
² Center for Computational Sciences, The Jackson Laboratory, Bar Harbor, Maine, USA.
³ Center for Mammalian Genetics, The Jackson Laboratory, Bar Harbor, Maine, USA.
⁴ Laboratory of Behavioral and Genomic Neuroscience, NIAAA, NIH, Rockville, MD, USA.
⁵ Department of Psychiatry, University of California San Diego, La Jolla, California, USA.
⁶ Institute for Genomic Medicine, University of California San Diego, La Jolla, California, USA.

Abstract

Background: A strong predictor for the development of alcohol use disorder (AUD) is altered sensitivity to the intoxicating effects of alcohol. Individual differences in the initial sensitivity to alcohol are controlled in part by genetic factors. Mice offer a powerful tool to elucidate the genetic basis of behavioral and physiological traits relevant to AUD, but conventional experimental crosses have only been able to identify large chromosomal regions rather than specific genes. Genetically diverse, highly recombinant mouse populations make it possible to observe a wider range of phenotypic variation, offer greater mapping precision, and thus increase the potential for efficient gene identification.

Methods: We have taken advantage of the Diversity Outbred (DO) mouse population to identify and precisely map quantitative trait loci (QTL) associated with ethanol sensitivity. We phenotyped 798 male J:DO mice for three measures of ethanol sensitivity: ataxia, hypothermia, and loss of the righting response. We used high-density MegaMUGA and GigaMUGA to obtain genotypes ranging from 77,808 to 143,259 SNPs. We also performed RNA sequencing in striatum to map expression QTLs and identify gene expression-trait correlations. We then applied a systems genetic strategy to identify narrow QTLs and construct the network of correlations that exists between DNA sequence, gene expression values, and ethanol-related phenotypes to prioritize our list of positional candidate genes.

Results: We observed large amounts of phenotypic variation with the DO population and identified suggestive and significant QTLs associated with ethanol sensitivity on chromosomes 1, 2, and 16. The implicated regions were narrow (4.5-6.9 Mb in size) and each QTL explained ~4-5% of the variance.

Conclusions: Our results can be used to identify alleles that contribute to AUD in humans, elucidate causative biological mechanisms, or assist in the development of novel therapeutic interventions.

Keywords: Diversity Outbred mice; GWAS; alcohol sensitivity; ethanol sensitivity; genetics.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alcoholism* / genetics
Animals
Chromosome Mapping / methods
Collaborative Cross Mice* / genetics
Ethanol / pharmacology
Genome-Wide Association Study
Male
Mice
Quantitative Trait Loci

Substances

Ethanol

Abstract

Publication types

MeSH terms

Substances

Grants and funding