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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 4 and human chromosome 9 quantitative trait loci (QTLs). Human chromosome 9 shares primary conserved regions with mouse chromosomes 1, 4, 19, 2, and 13, and mouse chromosome 4 shares regions syntenic with human chromosomes 9, 8, 1, and 6. For both mouse and human chromosomes additional smaller syntenic regions exist (not shown). Mouse chromosome 4 carries a significant QTL for ethanol withdrawal that has been mapped to 1.8-Mb interval. Within this interval, a gene called Mpdz has been identified as a quantitative trait gene (QTG) candidate for ethanol withdrawal (Shirley et al. 2004). The dashed red boxes and line denote this 1.8-Mb QTL interval and syntenic region on human chromosome 9 (9p23–p22.3). A recent human association study for alcohol consumption (Tabakoff et al. 2010) found significant association with a DNA variation (i.e., single nucleotide polymorphism [SNP]) within the human gene MPDZ (P < 0.0001). Sequence variations in human MPDZ also may be associated with alcohol dependence (Karpyak et al. 2010). Thus, this gene has been implicated in studies using animal model and clinical populations. Additional markers near this region of human chromosome 9 may be associated with alcohol-related phenotypes, including age of onset of use (D9S925; Williams et al. 2005), predisposition to alcohol dependence (D9S319; Long et al. 1998), and alcohol response (PTPRD; Joslyn et al. 2010).
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f2-arcr-34-3-367: Potential synteny between mouse chromosome 4 and human chromosome 9 quantitative trait loci (QTLs). Human chromosome 9 shares primary conserved regions with mouse chromosomes 1, 4, 19, 2, and 13, and mouse chromosome 4 shares regions syntenic with human chromosomes 9, 8, 1, and 6. For both mouse and human chromosomes additional smaller syntenic regions exist (not shown). Mouse chromosome 4 carries a significant QTL for ethanol withdrawal that has been mapped to 1.8-Mb interval. Within this interval, a gene called Mpdz has been identified as a quantitative trait gene (QTG) candidate for ethanol withdrawal (Shirley et al. 2004). The dashed red boxes and line denote this 1.8-Mb QTL interval and syntenic region on human chromosome 9 (9p23–p22.3). A recent human association study for alcohol consumption (Tabakoff et al. 2010) found significant association with a DNA variation (i.e., single nucleotide polymorphism [SNP]) within the human gene MPDZ (P < 0.0001). Sequence variations in human MPDZ also may be associated with alcohol dependence (Karpyak et al. 2010). Thus, this gene has been implicated in studies using animal model and clinical populations. Additional markers near this region of human chromosome 9 may be associated with alcohol-related phenotypes, including age of onset of use (D9S925; Williams et al. 2005), predisposition to alcohol dependence (D9S319; Long et al. 1998), and alcohol response (PTPRD; Joslyn et al. 2010).

Mentions: Several studies also have provided evidence for an association of markers on human chromosome 9p with alcoholism, but these associations only remain suggestive (Edenberg et al. 2010; Joslyn et al. 2010; Long et al. 1998; Williams et al. 2005). These markers potentially are syntenic with the mouse chromosome 4 QTL for which Mpdz has been proposed as a QTG (figure 2). In addition, limited human association studies using only small populations have implicated MPDZ as potentially involved in excessive alcohol consumption and risk for alcoholism (Karpyak et al. 2009; Tabakoff et al. 2009). Thus, this gene is a promising translational candidate for future work toward improving prevention and treatment of alcohol abuse in dependent individuals.


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 4 and human chromosome 9 quantitative trait loci (QTLs). Human chromosome 9 shares primary conserved regions with mouse chromosomes 1, 4, 19, 2, and 13, and mouse chromosome 4 shares regions syntenic with human chromosomes 9, 8, 1, and 6. For both mouse and human chromosomes additional smaller syntenic regions exist (not shown). Mouse chromosome 4 carries a significant QTL for ethanol withdrawal that has been mapped to 1.8-Mb interval. Within this interval, a gene called Mpdz has been identified as a quantitative trait gene (QTG) candidate for ethanol withdrawal (Shirley et al. 2004). The dashed red boxes and line denote this 1.8-Mb QTL interval and syntenic region on human chromosome 9 (9p23–p22.3). A recent human association study for alcohol consumption (Tabakoff et al. 2010) found significant association with a DNA variation (i.e., single nucleotide polymorphism [SNP]) within the human gene MPDZ (P < 0.0001). Sequence variations in human MPDZ also may be associated with alcohol dependence (Karpyak et al. 2010). Thus, this gene has been implicated in studies using animal model and clinical populations. Additional markers near this region of human chromosome 9 may be associated with alcohol-related phenotypes, including age of onset of use (D9S925; Williams et al. 2005), predisposition to alcohol dependence (D9S319; Long et al. 1998), and alcohol response (PTPRD; Joslyn et al. 2010).
© Copyright Policy - public-domain
Related In: Results  -  Collection

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

f2-arcr-34-3-367: Potential synteny between mouse chromosome 4 and human chromosome 9 quantitative trait loci (QTLs). Human chromosome 9 shares primary conserved regions with mouse chromosomes 1, 4, 19, 2, and 13, and mouse chromosome 4 shares regions syntenic with human chromosomes 9, 8, 1, and 6. For both mouse and human chromosomes additional smaller syntenic regions exist (not shown). Mouse chromosome 4 carries a significant QTL for ethanol withdrawal that has been mapped to 1.8-Mb interval. Within this interval, a gene called Mpdz has been identified as a quantitative trait gene (QTG) candidate for ethanol withdrawal (Shirley et al. 2004). The dashed red boxes and line denote this 1.8-Mb QTL interval and syntenic region on human chromosome 9 (9p23–p22.3). A recent human association study for alcohol consumption (Tabakoff et al. 2010) found significant association with a DNA variation (i.e., single nucleotide polymorphism [SNP]) within the human gene MPDZ (P < 0.0001). Sequence variations in human MPDZ also may be associated with alcohol dependence (Karpyak et al. 2010). Thus, this gene has been implicated in studies using animal model and clinical populations. Additional markers near this region of human chromosome 9 may be associated with alcohol-related phenotypes, including age of onset of use (D9S925; Williams et al. 2005), predisposition to alcohol dependence (D9S319; Long et al. 1998), and alcohol response (PTPRD; Joslyn et al. 2010).
Mentions: Several studies also have provided evidence for an association of markers on human chromosome 9p with alcoholism, but these associations only remain suggestive (Edenberg et al. 2010; Joslyn et al. 2010; Long et al. 1998; Williams et al. 2005). These markers potentially are syntenic with the mouse chromosome 4 QTL for which Mpdz has been proposed as a QTG (figure 2). In addition, limited human association studies using only small populations have implicated MPDZ as potentially involved in excessive alcohol consumption and risk for alcoholism (Karpyak et al. 2009; Tabakoff et al. 2009). Thus, this gene is a promising translational candidate for future work toward improving prevention and treatment of alcohol abuse in dependent individuals.

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