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

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.

Figure 1

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.

Figure 2

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).