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Discovering genes involved in alcohol dependence and other alcohol responses: role of animal models.

Buck KJ, Milner LC, Denmark DL, Grant SG, Kozell LB - Alcohol Res (2012)

Bottom Line: The genetic determinants of alcoholism still are largely unknown, hindering effective treatment and prevention.Subsequent work led to the identification of underlying quantitative trait genes (QTGs) (e.g., Mpdz) and high-quality QTG candidates (e.g., Kcnj9 and genes involved in mitochondrial respiration and oxidative stress) and their plausible mechanisms of action.Human association studies provide supporting evidence that these QTLs and QTGs may be directly relevant to alcohol risk factors in clinical populations.

View Article: PubMed Central - PubMed

Affiliation: Oregon Health & Science University, Portland, Oregon and the Department of Veterans Affairs Medical Center, Portland, Oregon.

ABSTRACT
The genetic determinants of alcoholism still are largely unknown, hindering effective treatment and prevention. Systematic approaches to gene discovery are critical if novel genes and mechanisms involved in alcohol dependence are to be identified. Although no animal model can duplicate all aspects of alcoholism in humans, robust animal models for specific alcohol-related traits, including physiological alcohol dependence and associated withdrawal, have been invaluable resources. Using a variety of genetic animal models, the identification of regions of chromosomal DNA that contain a gene or genes which affect a complex phenotype (i.e., quantitative trait loci [QTLs]) has allowed unbiased searches for candidate genes. Several QTLs with large effects on alcohol withdrawal severity in mice have been detected, and fine mapping of these QTLs has placed them in small intervals on mouse chromosomes 1 and 4 (which correspond to certain regions on human chromosomes 1 and 9). Subsequent work led to the identification of underlying quantitative trait genes (QTGs) (e.g., Mpdz) and high-quality QTG candidates (e.g., Kcnj9 and genes involved in mitochondrial respiration and oxidative stress) and their plausible mechanisms of action. Human association studies provide supporting evidence that these QTLs and QTGs may be directly relevant to alcohol risk factors in clinical populations.

No MeSH data available.


Related in: MedlinePlus

Potential synteny between mouse chromosome 1 and human chromosome 1 quantitative trait loci (QTLs). Human chromosome 1 shares primary conserved regions with mouse chromosomes 1, 3, and 4. Conversely, mouse chromosome 1 shares regions syntenic with human chromosomes 1, 2, 5, 6, 8, and 18. For both mouse and human chromosomes, additional smaller syntenic regions exist (not shown). Mouse chromosome 1 carries significant QTLs for physiological dependence and associated withdrawal following chronic and acute ethanol exposure, two of which have been finely mapped to small DNA intervals of 0.44 and 1.7 Mb (see blue and red lines next to mouse chromosome 1). High-quality quantitative trait gene (QTG) candidates have been identified within these two intervals, including Kcnj9 and genes involved in mitochondrial respiration and/or oxidative stress. (Denmark and Buck 2009; Kozell et al. 2009). Another QTL for ethanol consumption and withdrawal has also been detected nearby (see black line) but has not yet been finely mapped. The dashed red boxes and line denote the two finely mapped mouse QTL intervals and the syntenic region of human chromosome 1 (1q23.2–1q23.3). Two human QTL studies have determined peak log of the odds of linkage (LOD) scores for alcoholism (red line; Hill et al. 2004) and for age of onset of drinking, harm avoidance, novelty seeking, and alcohol dependence (blue line; Dick et al. 2002) in this human chromosome 1 region. Four genetic markers (rs1229430, rs2001270, rs3753563, and rs84465) that are associated (P < 0.0001) with heaviness of drinking, alcohol use disorder, and/or alcohol dependence (Heath et al. 2011) are located in that same region (green lines). Thus, one or more human QTLs may be narrowed to a small syntenic interval of human chromosome 1 that harbors the homologs of high-quality QTG candidates identified in mice.
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f1-arcr-34-3-367: Potential synteny between mouse chromosome 1 and human chromosome 1 quantitative trait loci (QTLs). Human chromosome 1 shares primary conserved regions with mouse chromosomes 1, 3, and 4. Conversely, mouse chromosome 1 shares regions syntenic with human chromosomes 1, 2, 5, 6, 8, and 18. For both mouse and human chromosomes, additional smaller syntenic regions exist (not shown). Mouse chromosome 1 carries significant QTLs for physiological dependence and associated withdrawal following chronic and acute ethanol exposure, two of which have been finely mapped to small DNA intervals of 0.44 and 1.7 Mb (see blue and red lines next to mouse chromosome 1). High-quality quantitative trait gene (QTG) candidates have been identified within these two intervals, including Kcnj9 and genes involved in mitochondrial respiration and/or oxidative stress. (Denmark and Buck 2009; Kozell et al. 2009). Another QTL for ethanol consumption and withdrawal has also been detected nearby (see black line) but has not yet been finely mapped. The dashed red boxes and line denote the two finely mapped mouse QTL intervals and the syntenic region of human chromosome 1 (1q23.2–1q23.3). Two human QTL studies have determined peak log of the odds of linkage (LOD) scores for alcoholism (red line; Hill et al. 2004) and for age of onset of drinking, harm avoidance, novelty seeking, and alcohol dependence (blue line; Dick et al. 2002) in this human chromosome 1 region. Four genetic markers (rs1229430, rs2001270, rs3753563, and rs84465) that are associated (P < 0.0001) with heaviness of drinking, alcohol use disorder, and/or alcohol dependence (Heath et al. 2011) are located in that same region (green lines). Thus, one or more human QTLs may be narrowed to a small syntenic interval of human chromosome 1 that harbors the homologs of high-quality QTG candidates identified in mice.

Mentions: As reviewed here, studies in mouse models of various aspects of alcohol dependence have identified several QTLs with large effects on ethanol physiological dependence and associated withdrawal, have reduced these QTLs to small intervals of chromosomes 1 and 4 (which are syntenic to human chromosomes 1q23.2–23.3 and 9p23–p22.3, respectively), and have led to the description of a QTG or high-quality QTG candidate(s). Human association studies have provided evidence that the QTLs and QTGs identified in mice may be relevant to risk factors for alcoholism in clinical populations. For example, two studies have identified DNA regions associated with alcohol dependence on human chromosome 1q (LOD>3), and additional studies have provided supporting evidence for the association of 1q markers with alcoholism (for reviews, see Edenberg et al. 2010; Ehlers et al. 2010; Hansell et al. 2009; Heath et al. 2011; Joslyn et al. 2010) (see figure 1). These loci potentially are syntenic with the identified mouse chromosome 1 QTLs for alcohol consumption and withdrawal (Ehlers et al. 2010).


Discovering genes involved in alcohol dependence and other alcohol responses: role of animal models.

Buck KJ, Milner LC, Denmark DL, Grant SG, Kozell LB - Alcohol Res (2012)

Potential synteny between mouse chromosome 1 and human chromosome 1 quantitative trait loci (QTLs). Human chromosome 1 shares primary conserved regions with mouse chromosomes 1, 3, and 4. Conversely, mouse chromosome 1 shares regions syntenic with human chromosomes 1, 2, 5, 6, 8, and 18. For both mouse and human chromosomes, additional smaller syntenic regions exist (not shown). Mouse chromosome 1 carries significant QTLs for physiological dependence and associated withdrawal following chronic and acute ethanol exposure, two of which have been finely mapped to small DNA intervals of 0.44 and 1.7 Mb (see blue and red lines next to mouse chromosome 1). High-quality quantitative trait gene (QTG) candidates have been identified within these two intervals, including Kcnj9 and genes involved in mitochondrial respiration and/or oxidative stress. (Denmark and Buck 2009; Kozell et al. 2009). Another QTL for ethanol consumption and withdrawal has also been detected nearby (see black line) but has not yet been finely mapped. The dashed red boxes and line denote the two finely mapped mouse QTL intervals and the syntenic region of human chromosome 1 (1q23.2–1q23.3). Two human QTL studies have determined peak log of the odds of linkage (LOD) scores for alcoholism (red line; Hill et al. 2004) and for age of onset of drinking, harm avoidance, novelty seeking, and alcohol dependence (blue line; Dick et al. 2002) in this human chromosome 1 region. Four genetic markers (rs1229430, rs2001270, rs3753563, and rs84465) that are associated (P < 0.0001) with heaviness of drinking, alcohol use disorder, and/or alcohol dependence (Heath et al. 2011) are located in that same region (green lines). Thus, one or more human QTLs may be narrowed to a small syntenic interval of human chromosome 1 that harbors the homologs of high-quality QTG candidates identified in mice.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3860408&req=5

f1-arcr-34-3-367: Potential synteny between mouse chromosome 1 and human chromosome 1 quantitative trait loci (QTLs). Human chromosome 1 shares primary conserved regions with mouse chromosomes 1, 3, and 4. Conversely, mouse chromosome 1 shares regions syntenic with human chromosomes 1, 2, 5, 6, 8, and 18. For both mouse and human chromosomes, additional smaller syntenic regions exist (not shown). Mouse chromosome 1 carries significant QTLs for physiological dependence and associated withdrawal following chronic and acute ethanol exposure, two of which have been finely mapped to small DNA intervals of 0.44 and 1.7 Mb (see blue and red lines next to mouse chromosome 1). High-quality quantitative trait gene (QTG) candidates have been identified within these two intervals, including Kcnj9 and genes involved in mitochondrial respiration and/or oxidative stress. (Denmark and Buck 2009; Kozell et al. 2009). Another QTL for ethanol consumption and withdrawal has also been detected nearby (see black line) but has not yet been finely mapped. The dashed red boxes and line denote the two finely mapped mouse QTL intervals and the syntenic region of human chromosome 1 (1q23.2–1q23.3). Two human QTL studies have determined peak log of the odds of linkage (LOD) scores for alcoholism (red line; Hill et al. 2004) and for age of onset of drinking, harm avoidance, novelty seeking, and alcohol dependence (blue line; Dick et al. 2002) in this human chromosome 1 region. Four genetic markers (rs1229430, rs2001270, rs3753563, and rs84465) that are associated (P < 0.0001) with heaviness of drinking, alcohol use disorder, and/or alcohol dependence (Heath et al. 2011) are located in that same region (green lines). Thus, one or more human QTLs may be narrowed to a small syntenic interval of human chromosome 1 that harbors the homologs of high-quality QTG candidates identified in mice.
Mentions: As reviewed here, studies in mouse models of various aspects of alcohol dependence have identified several QTLs with large effects on ethanol physiological dependence and associated withdrawal, have reduced these QTLs to small intervals of chromosomes 1 and 4 (which are syntenic to human chromosomes 1q23.2–23.3 and 9p23–p22.3, respectively), and have led to the description of a QTG or high-quality QTG candidate(s). Human association studies have provided evidence that the QTLs and QTGs identified in mice may be relevant to risk factors for alcoholism in clinical populations. For example, two studies have identified DNA regions associated with alcohol dependence on human chromosome 1q (LOD>3), and additional studies have provided supporting evidence for the association of 1q markers with alcoholism (for reviews, see Edenberg et al. 2010; Ehlers et al. 2010; Hansell et al. 2009; Heath et al. 2011; Joslyn et al. 2010) (see figure 1). These loci potentially are syntenic with the identified mouse chromosome 1 QTLs for alcohol consumption and withdrawal (Ehlers et al. 2010).

Bottom Line: The genetic determinants of alcoholism still are largely unknown, hindering effective treatment and prevention.Subsequent work led to the identification of underlying quantitative trait genes (QTGs) (e.g., Mpdz) and high-quality QTG candidates (e.g., Kcnj9 and genes involved in mitochondrial respiration and oxidative stress) and their plausible mechanisms of action.Human association studies provide supporting evidence that these QTLs and QTGs may be directly relevant to alcohol risk factors in clinical populations.

View Article: PubMed Central - PubMed

Affiliation: Oregon Health & Science University, Portland, Oregon and the Department of Veterans Affairs Medical Center, Portland, Oregon.

ABSTRACT
The genetic determinants of alcoholism still are largely unknown, hindering effective treatment and prevention. Systematic approaches to gene discovery are critical if novel genes and mechanisms involved in alcohol dependence are to be identified. Although no animal model can duplicate all aspects of alcoholism in humans, robust animal models for specific alcohol-related traits, including physiological alcohol dependence and associated withdrawal, have been invaluable resources. Using a variety of genetic animal models, the identification of regions of chromosomal DNA that contain a gene or genes which affect a complex phenotype (i.e., quantitative trait loci [QTLs]) has allowed unbiased searches for candidate genes. Several QTLs with large effects on alcohol withdrawal severity in mice have been detected, and fine mapping of these QTLs has placed them in small intervals on mouse chromosomes 1 and 4 (which correspond to certain regions on human chromosomes 1 and 9). Subsequent work led to the identification of underlying quantitative trait genes (QTGs) (e.g., Mpdz) and high-quality QTG candidates (e.g., Kcnj9 and genes involved in mitochondrial respiration and oxidative stress) and their plausible mechanisms of action. Human association studies provide supporting evidence that these QTLs and QTGs may be directly relevant to alcohol risk factors in clinical populations.

No MeSH data available.


Related in: MedlinePlus