Phenotypic and gene expression features associated with variation in chronic ethanol consumption in heterogeneous stock collaborative cross mice

Hitzemann, Robert; Phillips, Tamara J.; Lockwood, Denesa R.; Darakjian, Priscila; Searles, Robert P.

doi:10.1016/j.ygeno.2020.08.004

Cited by 17 publications

(20 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Research into benzene toxicity in DO mice revealed that harnessing this genetic heterogeneity in the mouse better reflected the diverse reactions to benzene exposure seen in humans (French et al, 2015). Efforts using heterogeneous stock (HS) mice, with similar genetic backgrounds as DO mice, have correlated genes with sex-specific ethanol preference and chronic consumption phenotypes, and similar results have been corroborated in DO mice (Hitzemann et al, 2020). In the context of SUD, DO mice may be used to study the interaction between host genes, the environment (i.e., microbiome), and phenotypic differences between strains that reflect similar genetic diversity in humans.…”

Section: Diversity Outbred Mouse Modelsmentioning

confidence: 97%

The Gut Microbiome and Substance Use Disorder

et al. 2021

View full text Add to dashboard Cite

Substance use disorders (SUDs) remain a significant public health challenge, affecting tens of millions of individuals worldwide each year. Often comorbid with other psychiatric disorders, SUD can be poly-drug and involve several different substances including cocaine, opiates, nicotine, and alcohol. SUD has a strong genetic component. Much of SUD research has focused on the neurologic and genetic facets of consumption behavior. There is now interest in the role of the gut microbiome in the pathogenesis of SUD. In this review, we summarize current animal and clinical evidence that the gut microbiome is involved in SUD, then address the underlying mechanisms by which the gut microbiome interacts with SUD through metabolomic, immune, neurological, and epigenetic mechanisms. Lastly, we discuss methods using various inbred and outbred mice models to gain an integrative understanding of the microbiome and host genetic controls in SUD.

show abstract

Section: Diversity Outbred Mouse Modelsmentioning

confidence: 97%

The Gut Microbiome and Substance Use Disorder

et al. 2021

View full text Add to dashboard Cite

show abstract

“…While this represents the first time the DO mice have been characterized for level of response to ethanol, others have studied the DO and related populations for additional ethanol-related traits. For example, Hitzemann et al (Hitzemann et al 2020) Collectively, these studies demonstrate the ways in the high genetic and phenotypic variation captured by these complementary mouse resources can be used to map genes and identify gene expression networks associated with ethanol-relevant traits.…”

Section: Qtl Mappingmentioning

confidence: 99%

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

Parker

Philip

Gatti

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: A strong predictor for the development of alcohol use disorders (AUDs) 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 for elucidating the genetic basis of behavioral and physiological traits relevant to AUDs; but conventional experimental crosses have only been able to identify large chromosomal regions rather than specific genes. Genetically diverse, highly recombinant mouse populations allow for the opportunity 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 arrays to obtain genotypes ranging from 77,808 to 143,259 SNPs. In addition, we performed RNA sequencing in striatum to map expression QTLs and to identify gene expression-trait correlations. Results: We then applied a systems genetic strategy to identify narrow QTLs and construct the network of correlations that exist between DNA sequence, gene expression values and ethanol related phenotypes to prioritize our list of positional candidate genes. Conclusions: Our results can be used to identify alleles that contribute to AUDs in humans, elucidate causative biological mechanisms, or assist in the development of novel therapeutic interventions.

show abstract

“…Both RI panels and heterogeneous stocks [94,[108][109][110][111][112][113][114][115][116][117][118][119] have been extensively studied for alcohol-related phenotypes. Furthermore all of these populations have been successfully used to map genes associated with psychiatric traits [63,91,100,101,[120][121][122][123][124] including addiction-related phenotypes [125].…”

Section: Forward Geneticsmentioning

confidence: 99%

Alcohol Sensitivity as an Endophenotype of Alcohol Use Disorder: Exploring Its Translational Utility between Rodents and Humans

2020

View full text Add to dashboard Cite

Alcohol use disorder (AUD) is a complex, chronic, relapsing disorder with multiple interacting genetic and environmental influences. Numerous studies have verified the influence of genetics on AUD, yet the underlying biological pathways remain unknown. One strategy to interrogate complex diseases is the use of endophenotypes, which deconstruct current diagnostic categories into component traits that may be more amenable to genetic research. In this review, we explore how an endophenotype such as sensitivity to alcohol can be used in conjunction with rodent models to provide mechanistic insights into AUD. We evaluate three alcohol sensitivity endophenotypes (stimulation, intoxication, and aversion) for their translatability across human and rodent research by examining the underlying neurobiology and its relationship to consumption and AUD. We show examples in which results gleaned from rodents are successfully integrated with information from human studies to gain insight in the genetic underpinnings of AUD and AUD-related endophenotypes. Finally, we identify areas for future translational research that could greatly expand our knowledge of the biological and molecular aspects of the transition to AUD with the broad hope of finding better ways to treat this devastating disorder.

show abstract

Phenotypic and gene expression features associated with variation in chronic ethanol consumption in heterogeneous stock collaborative cross mice

Cited by 17 publications

References 78 publications

The Gut Microbiome and Substance Use Disorder

The Gut Microbiome and Substance Use Disorder

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

Alcohol Sensitivity as an Endophenotype of Alcohol Use Disorder: Exploring Its Translational Utility between Rodents and Humans

Contact Info

Product

Resources

About