A systems genetic analysis of alcohol drinking by mice, rats and men: Influence of brain GABAergic transmission

Saba, Laura; Bennett, Beth; Hoffman, Paula L.; Barcomb, Kelsey; Ishii, Takao; Kechris, Katerina; Tabakoff, Boris

doi:10.1016/j.neuropharm.2010.12.019

Cited by 50 publications

(65 citation statements)

References 123 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alcohol withdrawal and preference are known to involve GABAergic transmission, whereby chronic alcohol alters GABA receptor subunit expression and potentiates the action of GABA at the receptors (Buck and Finn 2001;Nakatsu et al 2004;Finn et al 2006Finn et al , 2010Saba et al 2011;Sharp et al 2011;Enoch et al 2012). In the presence of low levels of alcohol, GABA-A binding is potentiated, as is Cl 2 influx through the GABA-A ion channel and resulting neuronal inhibition (Clapp et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Identification of a QTL in Mus musculus for Alcohol Preference, Withdrawal, and Ap3m2 Expression Using Integrative Functional Genomics and Precision Genetics

et al. 2014

View full text Add to dashboard Cite

Extensive genetic and genomic studies of the relationship between alcohol drinking preference and withdrawal severity have been performed using animal models. Data from multiple such publications and public data resources have been incorporated in the GeneWeaver database with .60,000 gene sets including 285 alcohol withdrawal and preference-related gene sets. Among these are evidence for positional candidates regulating these behaviors in overlapping quantitative trait loci (QTL) mapped in distinct mouse populations. Combinatorial integration of functional genomics experimental results revealed a single QTL positional candidate gene in one of the loci common to both preference and withdrawal. Functional validation studies in Ap3m2 knockout mice confirmed these relationships. Genetic validation involves confirming the existence of segregating polymorphisms that could account for the phenotypic effect. By exploiting recent advances in mouse genotyping, sequence, epigenetics, and phylogeny resources, we confirmed that Ap3m2 resides in an appropriately segregating genomic region. We have demonstrated genetic and alcohol-induced regulation of Ap3m2 expression. Although sequence analysis revealed no polymorphisms in the Ap3m2-coding region that could account for all phenotypic differences, there are several upstream SNPs that could. We have identified one of these to be an H3K4me3 site that exhibits strain differences in methylation. Thus, by making cross-species functional genomics readily computable we identified a common QTL candidate for two related bio-behavioral processes via functional evidence and demonstrate sufficiency of the genetic locus as a source of variation underlying two traits. FINDING the genetic and genomic basis for complex disorders has been a major challenge, particularly for behavioral traits. This is because the disorders are highly heterogeneous in their manifestation and regulation, requiring a match of numerous genes to many aspects of the disorders. A compelling approach to this problem lies in integration of numerous disparate data sets across species, each aimed at characterizing the mechanistic biological underpinnings for the behaviors underlying these disorders as modeled in various species. Alcoholism and alcohol use-related disorders are complex, heritable traits that have been the subject of extensive genomic and genetic investigations (Morozova et al. 2012). These traits are particularly challenging because of their heterogeneity and the presence of multiple overlapping subsystems that subserve them (Gould and Gottesman 2006;Crabbe 2012). Many rodent quantitative trait loci (QTL) have been mapped for alcohol-related traits (Ehlers et al. 2010), gene expression analyses have been performed in a variety of populations, and a long history of alcoholism genetics in humans has led to numerous genome-wide association studies (GWAS) or linkage studies (Enoch 2013). QTL mapping studies historically had very low resolution, and many have been performed using populations for which...

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of a QTL in Mus musculus for Alcohol Preference, Withdrawal, and Ap3m2 Expression Using Integrative Functional Genomics and Precision Genetics

et al. 2014

View full text Add to dashboard Cite

show abstract

“…109 The strongest target predictions across multiple software platforms were for miR-101a/b and miR-218. Subsequent studies to investigate the actual effects of these miRNAs on alcohol consumption will be necessary for confirmation.…”

Section: Mirnas In Substance Use Disordersmentioning

confidence: 99%

MicroRNAs in addiction: adaptation's middlemen?

Vaart

2011

Mol Psychiatry

View full text Add to dashboard Cite

A central question in addiction is how drug-induced changes in synaptic signaling are converted into long-term neuroadaptations. Emerging evidence reveals that microRNAs (miRNAs) have a distinct role in this process through rapid response to cellular signals and dynamic regulation of local mRNA transcripts. Because each miRNA can target hundreds of mRNAs, relative changes in the expression of miRNAs can greatly impact cellular responsiveness, synaptic plasticity and transcriptional events. These diverse consequences of miRNA action occur through coordination with genes implicated in addictions, the most compelling of these being the neurotrophin BDNF, the transcription factor cAMP-responsive element-binding protein (CREB) and the DNA-binding methyl CpG binding protein 2 (MeCP2). In this study, we review the recent progress in the understanding of miRNAs in general mechanisms of plasticity and neuroadaptation and then focus on specific examples of miRNA regulation in the context of addiction. We conclude that miRNA-mediated gene regulation is a conserved means of converting environmental signals into neuronal response, which holds significant implications for addiction and other psychiatric illnesses.

show abstract

“…Such Musunuru et al 2010). A few eQTL studies have also recently been carried out to identify candidate genes for behavioral QTL (Hitzemann et al 2004;De Jong et al 2011;Saba et al 2011;Kelly et al 2012).Here, we studied two lines of rats (Rattus norvegicus) that, starting from one wild population, have been selected for increased tameness and increased aggression toward humans, respectively. These experimental populations derive from the work of Dmitry K. Belyaev who, along with his famous related work in foxes (Belyaev 1979;Trut 1999), initiated the rat lines to study the evolution and underlying biological mechanisms of tameness as a crucial first step in animal domestication (Diamond 1999;Trut 1999;Wiener and Wilkinson 2011).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…This approach has been successfully applied to quantitative traits in different species, e.g., yeast (Perlstein et al 2007), rats (Hubner et al 2005;Heinig et al 2010), mice (Mehrabian et al 2005;Schadt et al 2005), and humans (Moffatt et al 2007;Musunuru et al 2010). A few eQTL studies have also recently been carried out to identify candidate genes for behavioral QTL (Hitzemann et al 2004;De Jong et al 2011;Saba et al 2011;Kelly et al 2012).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

Heyne

Lautenschlaeger²,

Nelson

et al. 2014

Preprint

View full text Add to dashboard Cite

Interindividual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F 2 intercross of two outbred lines of rats selected for tame and aggressive behavior toward humans for .64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F 2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F 2 animals, we identify the genes Gltscr2, Lgi4, Zfp40, and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals. B EHAVIORAL differences among members of a species are in part due to genetic variation. The identification of the genes and variants that influence behavior remains challenging. In human genome-wide association studies of psychiatric and cognitive traits, the identified loci typically explain only a small fraction of the heritability, i.e., the additive genetic contribution to the trait (Watanabe et al. 2007;Hovatta and Barlow 2008;Deary et al. 2009;Otowa et al. 2009;Calboli et al. 2010;Terracciano et al. 2010;Flint and Munafo 2013;Rietveld et al. 2013;Sokolowska and Hovatta 2013). In experimental crosses in model species, especially between inbred lines, the identified loci (termed quantitative trait loci, QTL), often explain much more of the heritability (Lynch and Walsh 1998). However, in this design the spatial resolution is limited-the QTL are wide and contain many, sometimes hundreds of genes. With the exception of a handful of identified genes with quantitative effects on behavioral traits (Yalcin et al. 2004;Watanabe et al. 2007;McGrath et al. 2009;Bendesky et al. 2012;Goodson et al. 2012), gene identification is particularly difficult for behavioral QTL that often have modest effect sizes (Flint 2003;Willis-Owen and Flint 2006;Wright et al. 2006;Hovatta and Barlow 2008).The causal variants within a QTL can alter the protein sequence encoded by a gene or affect gene expression. Such Musunuru et al. 2010). A few eQTL studies have also recently been carried out to identify candidate genes for behavioral QTL (Hitzemann et al. 2004;De Jong et al. 2011;Saba et al. 2011;Kelly et al. 2012).Here, we studied two lines of rats (Rattus norvegicus) that, starting from one wild population, have been selected for increased tameness and increased aggression toward humans, respectively. These experimental...

show abstract

A systems genetic analysis of alcohol drinking by mice, rats and men: Influence of brain GABAergic transmission

Cited by 50 publications

References 123 publications

Identification of a QTL in Mus musculus for Alcohol Preference, Withdrawal, and Ap3m2 Expression Using Integrative Functional Genomics and Precision Genetics

Identification of a QTL in Mus musculus for Alcohol Preference, Withdrawal, and Ap3m2 Expression Using Integrative Functional Genomics and Precision Genetics

MicroRNAs in addiction: adaptation's middlemen?

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

Contact Info

Product

Resources

About