A comparison of selected quantitative trait loci associated with alcohol use phenotypes in humans and mouse models

Abstract

Evidence for genetic linkage to alcohol and other substance dependence phenotypes in areas of the human and mouse genome have now been reported with some consistency across studies. However, the question remains as to whether the genes that underlie the alcohol-related behaviors seen in mice are the same as those that underlie the behaviors observed in human alcoholics. The aims of the current set of analyses were to identify a small set of alcohol-related phenotypes in human and in mouse by which to compare quantitative trait locus (QTL) data between the species using syntenic mapping. These analyses identified that QTLs for alcohol consumption and acute and chronic alcohol withdrawal on distal mouse chromosome 1 are syntenic to a region on human chromosome 1q where a number of studies have identified QTLs for alcohol-related phenotypes. Additionally, a QTL on human chromosome 15 for alcohol dependence severity/withdrawal identified in two human studies was found to be largely syntenic with a region on mouse chromosome 9, where two groups have found QTLs for alcohol preference. In both of these cases, while the QTLs were found to be syntenic, the exact phenotypes between humans and mice did not necessarily overlap. These studies demonstrate how this technique might be useful in the search for genes underlying alcohol-related phenotypes in multiple species. However, these findings also suggest that trying to match exact phenotypes in humans and mice may not be necessary or even optimal for determining whether similar genes influence a range of alcohol-related behaviors between the two species.

Figure 1

Synteny between human chromosome 15q and mouse chromosome 9 is illustrated with the colored bars. Proximally to distally, human chromosome 15 shares primary conserved regions with mouse chromosomes 7, 2, 9, and a different region of chromosome 7. Similarly, mouse chromosome 9 shares regions with human chromosomes 11, 19, 7, 15, 6, and 3. For both mouse and human there are smaller syntenic regions that we are not able to illustrate in detail here. Lines depicting LOD score plots are adapted from published QTLs to illustrate the statistical strength of linkage for human alcohol dependence QTLs (blue line from Ehlers et al. 2004; red line from Dick et al. 2002) shown to the left of human chromosome 15. The evident peaks were near 53 and 50 Mb, respectively. The analogous LOD plots for mouse alcohol preference QTLs are shown to the right of mouse chromosome 9 (orange line, Ap5q, from Tarantino et al. 1998; green line, Etp5, from Phillips et al. 1998). The dashed black boxes and line demonstrate the narrowed region of interest based upon mutual synteny of the mouse and human QTLs. The region of human chromosome 15 in the dashed black box is syntenic to the region of mouse chromosome 9 dashed black box, but in reverse orientation, so the most distal gene in human chromosome 15 region is the most proximal in mouse chromosome 9 region and vice versa. Comparison suggests that the human QTL is in the more proximal section of human 15 syntenic with mouse 9, and the more distal section of mouse 9 syntenic with human 15.

Figure 2

Synteny between human chromosome 1 and mouse chromosome 1 is illustrated with the colored bars. Human chromosome 1 shares primary conserved regions with mouse chromosomes 4, 3, and 1. Mouse chromosome 1 shares regions syntenic with human chromosomes 8, 6, 2, 5, 18, and 1. For both mouse and human there are smaller syntenic regions that we are not able to illustrate in detail here. Lines depicting LOD score plots are adapted from published QTLs to illustrate human alcohol dependence QTLs (blue line from Dick et al., 2002; red line from Hill et al., 2004) shown to the left of human chromosome 1. The red line to the right of mouse chromosome 1 shows the original 1-LOD confidence interval for the alcohol withdrawal QTL (Alcw1, Buck et al., 1997). Fine-mapping has delineated two QTLs (B and C with 1.7 Mb and 0.44 Mb QTL intervals, respectively) within the starting QTL region . The more proximal QTL (B) affects ethanol withdrawal, but not pentobarbital or zolpidem withdrawal (Kozell et al., 2008), while the more distal QTL (C) affects ethanol, pentobarbital, and zolpidem withdrawal (Kozell et al., 2009). Both QTLs are syntenic to human chromosome 1q23.2-1q23.3. Additionally, two reciprocal, coincident QTLs for ethanol consumption and ethanol withdrawal are located within this region (Hitzemann et al., 2009); the positions of the peak LOD values are indicated because these QTLs are not yet fine-mapped (A and D). The dashed black boxes and line indicate the QTL intervals on mouse (A, B, and also C) and human based on the fine mapping of the mouse QTLs and synteny with human distal chromosome 1. The region of mouse chromosome 1 in the dashed black box is syntenic to the region of human chromosome 1 dashed black box, but in reverse orientation, so the most distal gene in mouse chromosome 1 region is the most proximal in human chromosome 1 region and vice versa. Additionally, the most distal mouse QTL peak (D) is syntenic to very distal human chromosome 1 and is not included in the synteny block shown. Comparison of the narrowed mouse QTL on chromosome 1 with the human QTL suggests that the human QTL can also be narrowed to the small region on chromosome 1.