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The Genetics of Alcohol Use Disorder

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A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Molecular and Cellular Neuroscience".

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 25144

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Dr. Julia A. Chester

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Guest Editor

Department of Psychological Sciences, Purdue University, West Lafayette, IN 47907, USA
Interests: alcohol use disorders; psychiatric disorders; sex differences; stress; genetics; pharmacology; reward; aversion; animal modeling

Special Issue Information

Dear Colleagues,

Alcohol use disorders arise through a complex interplay between genetic and environmental factors to influence their development, maintenance, and treatment outcomes. Over the last three decades, knowledge regarding the genetic underpinnings of alcohol use disorder has come about through research methods in behavior genetics, gene linkage and mapping analyses, and transgenic animal models. Recent technological advances have allowed for increasingly sophisticated approaches that combine classical methods with tools such as transcriptomic, epigenetic, and optogenetic analyses to understand complex gene networks and genetic controls at the cellular level. Although sex differences in the incidence and severity of alcohol use disorders are well known, with males at higher risk than females, the majority of data collected to date is still predominantly from male subjects. However, recent trends indicate a concerning upward trajectory in the incidence of alcohol use disorders among females, particularly in adolescent populations, necessitating replication and expansion of research designs that include female subjects. Collaborative and multidisciplinary research is progressing at a rapid rate to identify key combinations of genetic and epigenetic factors along with environmental variables that influence vulnerability toward alcohol use disorders.

This Special Issue will highlight findings in both human and nonhuman animal models that demonstrate, using a variety of methodological approaches, the complex interplay between genetic and environmental variables, as well as ontogenetic and biological factors, that influence the incidence and severity of alcohol use disorders and their treatment outcomes. We invite research articles, review articles, and short communications.

Dr. Julia A. Chester
Guest Editor

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Keywords

Behavioral genetics
Epigenetics
Genomics
Gene x environment interactions
Ontogeny
Pharmacogenetics
Sex differences

Published Papers (9 papers)

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Research

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16 pages, 1356 KiB

Open AccessArticle

Modeling Aversion Resistant Alcohol Intake in Indiana Alcohol-Preferring (P) Rats

by Simon N. Katner, Alena M. Sentir, Kevin B. Steagall, Zheng-Ming Ding, Leah Wetherill, Frederic W. Hopf and Eric A. Engleman

Brain Sci. 2022, 12(8), 1042; https://doi.org/10.3390/brainsci12081042 - 05 Aug 2022

Cited by 7 | Viewed by 2136

Abstract

With the substantial social and medical burden of addiction, there is considerable interest in understanding risk factors that increase the development of addiction. A key feature of alcohol use disorder (AUD) is compulsive alcohol (EtOH) drinking, where EtOH drinking becomes “inflexible” after chronic intake, and animals, such as humans with AUD, continue drinking despite aversive consequences. Further, since there is a heritable component to AUD risk, some work has focused on genetically-selected, EtOH-preferring rodents, which could help uncover critical mechanisms driving pathological intake. In this regard, aversion-resistant drinking (ARD) takes >1 month to develop in outbred Wistar rats (and perhaps Sardinian-P EtOH-preferring rats). However, ARD has received limited study in Indiana P-rats, which were selected for high EtOH preference and exhibit factors that could parallel human AUD (including front-loading and impulsivity). Here, we show that P-rats rapidly developed compulsion-like responses for EtOH; 0.4 g/L quinine in EtOH significantly reduced female and male intake on the first day of exposure but had no effect after one week of EtOH drinking (15% EtOH, 24 h free-choice paradigm). Further, after 4–5 weeks of EtOH drinking, males but not females showed resistance to even higher quinine (0.5 g/L). Thus, P-rats rapidly developed ARD for EtOH, but only males developed even stronger ARD with further intake. Finally, rats strongly reduced intake of quinine-adulterated water after 1 or 5 weeks of EtOH drinking, suggesting no changes in basic quinine sensitivity. Thus, modeling ARD in P-rats may provide insight into mechanisms underlying genetic predispositions for compulsive drinking and lead to new treatments for AUDs. Full article

(This article belongs to the Special Issue The Genetics of Alcohol Use Disorder)

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18 pages, 2110 KiB

Open AccessArticle

Chronic Alcohol Use Induces Molecular Genetic Changes in the Dorsomedial Thalamus of People with Alcohol-Related Disorders

by Andreas-Christian Hade, Mari-Anne Philips, Ene Reimann, Toomas Jagomäe, Kattri-Liis Eskla, Tanel Traks, Ele Prans, Sulev Kõks, Eero Vasar and Marika Väli

Brain Sci. 2021, 11(4), 435; https://doi.org/10.3390/brainsci11040435 - 29 Mar 2021

Cited by 4 | Viewed by 2714

Abstract

The Mediodorsal (MD) thalamus that represents a fundamental subcortical relay has been underrepresented in the studies focusing on the molecular changes in the brains of subjects with alcohol use disorder (AUD). In the current study, MD thalamic regions from AUD subjects and controls were analyzed with Affymetrix Clariom S human microarray. Long-term alcohol use induced a significant (FDR ≤ 0.05) upregulation of 2802 transcripts and downregulation of 1893 genes in the MD thalamus of AUD subjects. A significant upregulation of GRIN1 (glutamate receptor NMDA type 1) and FTO (alpha-ketoglutarate dependent dioxygenase) was confirmed in western blot analysis. Immunohistochemical staining revealed similar heterogenous distribution of GRIN1 in the thalamic nuclei of both AUD and control subjects. The most prevalent functional categories of upregulated genes were related to glutamatergic and GABAergic neurotransmission, cellular metabolism, and neurodevelopment. The prevalent gene cluster among down-regulated genes was immune system mediators. Forty-two differentially expressed genes, including FTO, ADH1B, DRD2, CADM2, TCF4, GCKR, DPP6, MAPT and CHRH1, have been shown to have strong associations (FDR p < 10⁻⁸) with AUD or/and alcohol use phenotypes in recent GWA studies. Despite a small number of subjects, we were able to detect robust molecular changes in the mediodorsal thalamus caused by alcohol emphasizing the importance of deeper brain structures such as diencephalon, in the development of AUD-related dysregulation of neurocircuitry. Full article

(This article belongs to the Special Issue The Genetics of Alcohol Use Disorder)

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23 pages, 4188 KiB

Open AccessArticle

by Bryan E. Jensen, Kayla G. Townsley, Kolter B. Grigsby, Pamela Metten, Meher Chand, Miracle Uzoekwe, Alex Tran, Evan Firsick, Katherine LeBlanc, John C. Crabbe and Angela R. Ozburn

Brain Sci. 2021, 11(2), 189; https://doi.org/10.3390/brainsci11020189 - 04 Feb 2021

Cited by 8 | Viewed by 2720

Abstract

Alcohol use disorder (AUD) is a devastating psychiatric disorder that has significant wide-reaching effects on individuals and society. Selectively bred mouse lines are an effective means of exploring the genetic and neuronal mechanisms underlying AUD and such studies are translationally important for identifying treatment options. Here, we report on behavioral characterization of two replicate lines of mice that drink to intoxication, the High Drinking in the Dark (HDID)-1 and -2 mice, which have been selectively bred (20+ generations) for the primary phenotype of reaching high blood alcohol levels (BALs) during the drinking in the dark (DID) task, a binge-like drinking assay. Along with their genetically heterogenous progenitor line, Hs/Npt, we tested these mice on: DID and drinking in the light (DIL); temporal drinking patterns; ethanol sensitivity, through loss of righting reflex (LORR); and operant self-administration, including fixed ratio (FR1), fixed ratio 3:1 (FR3), extinction/reinstatement, and progressive ratio (PR). All mice consumed more ethanol during the dark than the light and both HDID lines consumed more ethanol than Hs/Npt during DIL and DID. In the dark, we found that the HDID lines achieved high blood alcohol levels early into a drinking session, suggesting that they exhibit front loading like drinking behavior in the absence of the chronicity usually required for such behavior. Surprisingly, HDID-1 (female and male) and HDID-2 (male) mice were more sensitive to the intoxicating effects of ethanol during the dark (as determined by LORR), while Hs/Npt (female and male) and HDID-2 (female) mice appeared less sensitive. We observed lower HDID-1 ethanol intake compared to either HDID-2 or Hs/Npt during operant ethanol self-administration. There were no genotype differences for either progressive ratio responding, or cue-induced ethanol reinstatement, though the latter is complicated by a lack of extinguished responding behavior. Taken together, these findings suggest that genes affecting one AUD-related behavior do not necessarily affect other AUD-related behaviors. Moreover, these findings highlight that alcohol-related behaviors can also differ between lines selectively bred for the same phenotype, and even between sexes within those same line. Full article

(This article belongs to the Special Issue The Genetics of Alcohol Use Disorder)

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11 pages, 1785 KiB

Open AccessArticle

Genetic and Pharmacological Manipulations of Glyoxalase 1 Mediate Ethanol Withdrawal Seizure Susceptibility in Mice

by Amanda M. Barkley-Levenson, Amy Lee and Abraham A. Palmer

Brain Sci. 2021, 11(1), 127; https://doi.org/10.3390/brainsci11010127 - 19 Jan 2021

Cited by 3 | Viewed by 2211

Abstract

Central nervous system (CNS) hyperexcitability is a clinically significant feature of acute ethanol withdrawal. There is evidence for a genetic contribution to withdrawal severity, but specific genetic risk factors have not been identified. The gene glyoxalase 1 (Glo1) has been previously implicated in ethanol consumption in mice, and GLO1 inhibition can attenuate drinking in mice and rats. Here, we investigated whether genetic and pharmacological manipulations of GLO1 activity can also mediate ethanol withdrawal seizure severity in mice. Mice from two transgenic lines overexpressing Glo1 on different genetic backgrounds (C57BL/6J (B6) and FVB/NJ (FVB)) were tested for handling-induced convulsions (HICs) as a measure of acute ethanol withdrawal. Following an injection of 4 g/kg alcohol, both B6 and FVB mice overexpressing Glo1 showed increases in HICs compared to wild-type littermates, though only the FVB line showed a statistically significant difference. We also administered daily ethanol injections (2 g/kg + 9 mg/kg 4-methylpyrazole) to wild-type B6 mice for 10 days and tested them for HICs on the 10th day following treatment with either a vehicle or a GLO1 inhibitor (S-bromobenzylglutathione cyclopentyl diester (pBBG)). Treatment with pBBG reduced HICs, although this effect was only statistically significant following two 10-day cycles of ethanol exposure and withdrawal. These results provide converging genetic and pharmacological evidence that GLO1 can mediate ethanol withdrawal seizure susceptibility. Full article

(This article belongs to the Special Issue The Genetics of Alcohol Use Disorder)

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15 pages, 1455 KiB

Open AccessArticle

Dimensions of Craving Interact with COMT Genotype to Predict Relapse in Individuals with Alcohol Use Disorder Six Months after Treatment

by Claudia B. Padula, Annika Hansen, Rachel L. Hughes and M. Windy McNerney

Brain Sci. 2021, 11(1), 62; https://doi.org/10.3390/brainsci11010062 - 06 Jan 2021

Cited by 1 | Viewed by 2349

Abstract

(1) Background: Alcohol use disorder (AUD) is associated with poor medical, psychological, and psychosocial outcomes and approximately 60% of individuals with AUD relapse six months after treatment. Craving is a core aspect of AUD and associated with high risk of relapse. One promising avenue to improve outcomes may be in understanding the relationship between COMT genotype, craving, and treatment outcomes. (2) Methods: To this end, we assessed craving, recent drinking history, and impulsivity in 70 individuals with AUD undergoing a standard course of treatment at a regional Veteran Affairs (VA) medical center. Saliva samples were collected to determine COMT genotype. In this prospective observational study, participants were followed for six months to determine who went on to relapse after treatment. (3) Results: Results revealed a significant interaction between craving and catechol-O-methyltransferse (COMT) genotype in predicting relapse. Post hoc exploratory analyses indicated that Met/Met homozygotes reported the highest levels of craving, and craving was associated with recent drinking history. Among Val/Val homozygotes, who had higher rates of relapse, craving was associated with impulsivity. (4) Conclusions: These associations highlight that specific profiles of psychological and biological factors may be important in understanding which individuals are at highest risk of relapse following treatment. Future studies that build on these findings are warranted. Full article

(This article belongs to the Special Issue The Genetics of Alcohol Use Disorder)

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14 pages, 284 KiB

Open AccessArticle

Interest in Genetic Feedback for Alcohol Use Disorder and Related Substance Use and Psychiatric Outcomes among Young Adults

by Morgan N. Driver, Sally I-Chun Kuo, Danielle M. Dick and on behalf of the Spit for Science Working Group

Brain Sci. 2020, 10(12), 1007; https://doi.org/10.3390/brainsci10121007 - 18 Dec 2020

Cited by 7 | Viewed by 2145

Abstract

An exponential growing number of individuals are accessing genetic risk information via direct to consumer companies. Alcohol dependence is the third most accessed genetic risk score on a publicly available direct to consumer website. Better understanding of the degree to which individuals are interested in receiving personalized genetic feedback, the factors that relate to interest, and genetic knowledge will be critical to lay the foundation for precision medicine initiatives, especially for substance use and psychiatric outcomes, where less is known. To assess interest in receiving genetic feedback for alcohol use disorder (AUD) and understanding of genetic concepts related to psychiatric conditions, we conducted a survey with participants recruited from a registry that enrolled incoming cohorts of freshmen at an urban public university; 205 participants (76.5% female; 58.9% self-reported as White; M_age = 24.48 years) completed the survey. Results indicated that participants are highly interested in receiving genetic feedback for AUD (79.0%) but there is a lack of understanding of complex genetic concepts in a sizable proportion of the sample (25.4%). Additional research is needed to assess how to address this lack of knowledge before genetic feedback for AUD can be returned in a way that benefits the individual. Full article

(This article belongs to the Special Issue The Genetics of Alcohol Use Disorder)

24 pages, 7144 KiB

Open AccessArticle

Distinct and Overlapping Patterns of Acute Ethanol-Induced C-Fos Activation in Two Inbred Replicate Lines of Mice Selected for Drinking to High Blood Ethanol Concentrations

by Stacey L. Robinson, Ana Paula S. Dornellas, Nathan W. Burnham, Christa A. Houck, Kendall L. Luhn, Sophie C. Bendrath, Michel A. Companion, Honoreé W. Brewton, Rhiannon D. Thomas, Montserrat Navarro and Todd E. Thiele

Brain Sci. 2020, 10(12), 988; https://doi.org/10.3390/brainsci10120988 - 15 Dec 2020

Cited by 14 | Viewed by 3023

Abstract

The inbred high drinking in the dark (iHDID1 and iHDID2) strains are two replicate lines bred from the parent HS/Npt (HS) line for achieving binge levels of blood ethanol concentration (≥80 mg/dL BEC) in a four-hour period. In this work, we sought to evaluate differences in baseline and ethanol-induced c-Fos activation between the HS, iHDID1, and iHDID2 genetic lines in brain regions known to process the aversive properties of ethanol. Methods: Male and female HS, iHDID1, and iHDID2 mice underwent an IP saline 2 3 g/kg ethanol injection. Brain sections were then stained for c-Fos expression in the basolateral/central amygdala (BLA/CeA), bed nucleus of the stria terminals (BNST), A2, locus coeruleus (LC), parabrachial nucleus (PBN), lateral/medial habenula (LHb/MHb), paraventricular nucleus of the thalamus (PVT), periaqueductal gray (PAG), Edinger–Westphal nuclei (EW), and rostromedial tegmental nucleus (RMTg). Results: The iHDID1 and iHDID2 lines showed similar and distinct patterns of regional c-Fos; however, in no region did the two both significantly differ from the HS line together. Conclusions: Our findings lend further support to the hypothesis the iHDID1 and the iHDID2 lines arrive at a similar behavior phenotype through divergent genetic mechanisms. Full article

(This article belongs to the Special Issue The Genetics of Alcohol Use Disorder)

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23 pages, 3625 KiB

Open AccessArticle

Effects of Paternal Preconception Vapor Alcohol Exposure Paradigms on Behavioral Responses in Offspring

by Richa S. Rathod, Carolyn Ferguson, Amit Seth, Annalisa M. Baratta, Sonja L. Plasil and Gregg E. Homanics

Brain Sci. 2020, 10(9), 658; https://doi.org/10.3390/brainsci10090658 - 22 Sep 2020

Cited by 9 | Viewed by 2866

Abstract

We and others previously reported that paternal preconception chronic ethanol exposure leads to molecular, physiological, and behavioral changes in offspring including reduced ethanol consumption and preference relative to controls. The goal of the present study was to further explore the impact of paternal ethanol exposure on a wide variety of basal and drug-induced behavioral responses in first generation offspring. Adult male mice were exposed to chronic intermittent vapor ethanol or control conditions for 5–6 weeks before being mated with ethanol-naïve females to produce ethanol (E)- and control (C)-sired offspring. E-sired male offspring showed stress hyporesponsivity in a stress-induced hyperthermia assay and E-sired female offspring had reduced binge-like ethanol consumption in a drinking in the dark assay compared to C-sired offspring. E-sired offspring also showed altered sensitivity to a sedative/hypnotic dose of the GABAergic drug midazolam, but not ketamine or ethanol, in a loss of the righting response assay. E-sired offspring did not differ from controls in marble burying, novel object location, novel object recognition, social interaction, bottle-brush, novelty suppressed feeding, prepulse inhibition, every-other-day ethanol drinking, or home cage activity assays. This study adds to a growing body of literature suggesting that like in utero alcohol exposure, paternal preconception alcohol exposure can also have effects that persist and impact behavior of offspring. Full article

(This article belongs to the Special Issue The Genetics of Alcohol Use Disorder)

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28 pages, 786 KiB

Open AccessReview

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

by Clarissa C. Parker, Ryan Lusk and Laura M. Saba

Brain Sci. 2020, 10(10), 725; https://doi.org/10.3390/brainsci10100725 - 13 Oct 2020

Cited by 10 | Viewed by 3812

Abstract

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. Full article

(This article belongs to the Special Issue The Genetics of Alcohol Use Disorder)

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