Identification and Confirmation of Quantitative Trait Loci Regulating Alcohol Consumption in Congenic Strains of Mice

Vj, Whatley; Te, Johnson; Vg, Erwin

doi:10.1111/j.1530-0277.1999.tb04287.x

Cited by 40 publications

(30 citation statements)

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“…The NT system is involved in a number of processes including sensorimotor gating, nociception, and in the pharmacological responses to both therapeutic agents and drugs of abuse, and therefore QTL that impact these types of phenotypes could be detecting the same underlying genes as the QTL controlling the NT system. Four QTL impacting responses to intoxicating substances, Alcp4, Alcp25, Morph1, and Cocia4 reside on proximal chromosome 1 within the NTta QTL located there (Whatley et al, 1999;Bergeson et al, 2001;Gill and Boyle, 2003). The Morph1 QTL is related to morphine-induced antinociception, the Alcp QTL are involved in gender-specific alcohol preference and Cocia4 impacts psychomotor stimulant effects of cocaine.…”

Section: Discussionmentioning

confidence: 99%

Genetic Analysis of the Hypothalamic Neurotensin System

Garlow

Boone

Kinkead

et al. 2005

Neuropsychopharmacol

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This study used B Â D recombinant inbred mice to detect and localize genes that control the hypothalamic neurotensin (NT) system. Abundance of transcripts that encode NT and NT receptors 1, 2, and 3 (NTR1, NTR2, and NTR3) in total hypothalamic RNA was the quantitative trait measured. Analysis of transcript abundance data revealed associations with quantitative trait loci (QTL) for NT transcript abundance (NTta) on chromosome 1, 3, 6, 7, 8, and 9; for NTR1ta on chromosome 3, 8, 12, and X; for NTR2ta on chromosome 2, 4, 9, 10, 12, 13, and 17; for NTR3ta on chromosome 1, 7, 11, and 12. NTta QTL on chromosomes 3, 7, and 8 coincide with QTL previously identified that impact NT peptide content and NTR2ta QTL on chromosome 2 and 12 coincide with genes previously associated with NTR2 receptor abundance. The NTta, NTR1ta, and NTR3ta QTL were not linked to their respective structural genes, but there is a highly significant (po0.001) association for NTR2ta on chromosome 12 that includes the Ntsr2 structural gene. There are areas of potential shared genetic regulation between NTta and NTR3ta on chromosome 1 and 7 and for all three receptors on proximal chromosome 12. The NTta QTL on chromosome 9 includes the dopamine D2 receptor (Drd2) gene and QTL involved in responses to dopaminergic agents (Hts), antipsychotics (Hpic1) and cocaine (Cocrb8), and ethanol (Etohc3). These results further strengthen the hypothesis that the NT system is involved in mediating the actions of antipsychotic agents and drugs of abuse.

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Section: Discussionmentioning

confidence: 99%

Genetic Analysis of the Hypothalamic Neurotensin System

Garlow

Boone

Kinkead

et al. 2005

Neuropsychopharmacol

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“…In most ethanol preference QTL studies, ∼2-3-month-old mice were phenotyped (Phillips et al 1994;Belknap et al 1997;Gill et al 1998;Tarantino et al 1998;Whatley et al 1999), although sometimes up to 9-month-old mice were used (Peirce et al 1998). Here, we used ∼7-month-old mice, so this also may have contributed to the different loci detected compared with the other studies.…”

Section: Alcohol Consumption Qtl In Micementioning

confidence: 99%

“…Of the three significant linkages identified in this study, only one, on distal chromosome 4, also was found to be linked to ethanol intake in the previous studies . The suggestive linkage on chromosome 2 (3% and 10% ethanol preference) may be equivalent to Alcp1/Pref2 (Phillips et al 1994(Phillips et al , 1998Melo et al 1996;Belknap et al 1997;Whatley Figure 5 Significant linkages. Left panels show results of interval mapping.…”

Section: Alcohol Consumption Qtl In Micementioning

confidence: 99%

“…In mice, the C57BL/6 strain has been most commonly used as one parent because of its high ethanol consumption. In most studies, the low-preferring strain used has been DBA/2 (e.g., Phillips et al 1994Phillips et al , 1998Melo et al 1996;Belknap et al 1997;Tarantino et al 1998;Whatley et al 1999), with a few exceptions (Gill et al 1998;Vadasz et al, 2000). In this study, we produced an F 2 intercross of the high ethanol-preferring C57BL/6ByJ (B6) strain with the 129P3/J (129) strain, which has low ethanol consumption (Belknap et al 1993;Bachmanov et al 1996bBachmanov et al , 2000Logue et al 1998) and had not been used previously in ethanol-related mapping studies.…”

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confidence: 99%

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Voluntary Ethanol Consumption by Mice: Genome-Wide Analysis of Quantitative Trait Loci and Their Interactions in a C57BL/6ByJ × 129P3/J F₂Intercross

Bachmanov

Reed²,

Li³

et al. 2002

Genome Res.

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Consumption of ethanol solutions by rodents in two-bottle choice tests is a model to study human alcohol intake. Mice of the C57BL/6ByJ strain have higher ethanol preferences and intakes than do mice of the 129P3/J strain. F 2 hybrids between these two strains were phenotyped using two-bottle tests involving a choice between water and either 3% or 10% ethanol. High ethanol preferences and intakes of the B6 mice were inherited as additive or dominant traits in the F 2 generation. A genome screen using these F 2 mice identified three significant linkages. Two loci, on distal chromosome 4 (Ap3q) and proximal chromosome 7 (Ap7q), strongly affected 10% ethanol intake and weakly affected 3% ethanol intake. A male-specific locus on proximal chromosome 8 (Ap8q) affected 3% ethanol preference, but not indexes of 10% ethanol consumption. In addition, six suggestive linkages (on chromosomes 2, 9, 12, 13, 17, and 18) affecting indexes of 3% and/or 10% ethanol consumption were detected. The loci with significant and suggestive linkages accounted for 35-44% of the genetic variation in ethanol consumption phenotypes. No additive-by-additive epistatic interactions were detected for the primary loci with significant and suggestive linkages. However, there were a few modifiers of the primary linkages and a number of interactions among unlinked loci. This demonstrates a significant role of the genetic background in the variation of ethanol consumption.

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“…A third line of evidence for a substantial genetic contribution to alcohol dependence comes from animal research. In selectively bred rodent lines, a considerable proportion of heritability in the development of addiction-related behavior has been observed, including strong preference for alcohol over water, willingness to work for alcohol, sensitivity to the hypnotic or activating effects of alcohol and to withdrawal, and demonstrations that alcohol is rewarding even in the presence of food and water [22,23,24,25,26]. A fourth line of evidence comes from early genetic studies in humans that demonstrated genetic variations in genes related to alcohol metabolism that affect the predisposition to alcohol dependence [27,28,29,30].…”

Section: Introductionmentioning

confidence: 99%

Genetics of Alcohol Dependence: A Review of Clinical Studies

Samochowiec

Puls

et al. 2014

Neuropsychobiology

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Background/Aims: Alcohol dependence is a common severe psychiatric disorder with a multifactorial etiology. Since the completion of the human genome project and with the increased availability of high-throughput genotyping, multiple genetic risk factors for substance-related disorders, including alcohol dependence, have been identified, but not all results could be replicated. Methods: We systematically review the clinical literature on genetic risk factors for alcohol dependence and alcohol-related phenotypes, including candidate gene-based studies, linkage studies and genome-wide association studies (GWAS). Results: Irrespectively of the methodology employed, the most robust findings regarding genetic risk factors for alcohol dependence concern genetic variations that affect alcohol metabolism. GWAS confirm the importance of the alcohol dehydrogenase gene cluster on chromosome 4 in the genetic risk for alcohol dependence with multiple variants that exert a small, but cumulative influence. A single variant with strong influence on individual risk is the aldehyde dehydrogenase 2 ALDHD2*2 variant common in Asian populations. Other robust associations have been found with previously uncharacterized genes like KIAA0040, and such observations can lead to the identification of thus far unknown signaling pathways. Converging evidence also points to a role of glutamatergic, dopaminergic and serotonergic neurotransmitter signaling in the risk for alcohol dependence, but effects are small, and gene-environment interactions further increase the complexity. Conclusion: With few exceptions like ALDH2*2, the contribution of individual genetic variants to the risk for alcohol-related disorders is small. However, the concentration of risk variants within neurotransmitter signaling pathways may help to deepen our understanding of the underlying pathophysiology and thereby contribute to develop novel therapeutic strategies.

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Identification and Confirmation of Quantitative Trait Loci Regulating Alcohol Consumption in Congenic Strains of Mice

Abstract: The QTL on chromosome 2 overlaps the 95% confidence interval of Alcp1 whereas that on chromosome 1 is new and has been called Alcp5. Marker-assisted selection was used in the N9 and subsequent generations to maintain the congenic lines and produce congenic strains.

Cited by 40 publications

References 46 publications

Genetic Analysis of the Hypothalamic Neurotensin System

Genetic Analysis of the Hypothalamic Neurotensin System

Voluntary Ethanol Consumption by Mice: Genome-Wide Analysis of Quantitative Trait Loci and Their Interactions in a C57BL/6ByJ × 129P3/J F₂Intercross

Genetics of Alcohol Dependence: A Review of Clinical Studies

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Identification and Confirmation of Quantitative Trait Loci Regulating Alcohol Consumption in Congenic Strains of Mice

Abstract: The QTL on chromosome 2 overlaps the 95% confidence interval of Alcp1 whereas that on chromosome 1 is new and has been called Alcp5. Marker-assisted selection was used in the N9 and subsequent generations to maintain the congenic lines and produce congenic strains.

Cited by 40 publications

References 46 publications

Genetic Analysis of the Hypothalamic Neurotensin System

Genetic Analysis of the Hypothalamic Neurotensin System

Voluntary Ethanol Consumption by Mice: Genome-Wide Analysis of Quantitative Trait Loci and Their Interactions in a C57BL/6ByJ × 129P3/J F2Intercross

Genetics of Alcohol Dependence: A Review of Clinical Studies

Contact Info

Product

Resources

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Voluntary Ethanol Consumption by Mice: Genome-Wide Analysis of Quantitative Trait Loci and Their Interactions in a C57BL/6ByJ × 129P3/J F₂Intercross