Rats offer clues to biology of alcoholism

Alcoholism may stem from using genes incorrectly, a study of hard-drinking rats suggests.

Rats bred either to drink heavily or to shun alcohol have revealed 930 genes linked to a preference for drinking alcohol, researchers in Indiana report August 4 in PLOS Genetics.

Human genetic studies have not found most of the genetic variants that put people at risk for alcoholism, says Michael Miles, a neurogenomicist at Virginia Commonwealth University in Richmond. The new study takes a “significant and somewhat novel approach” to find the genetic differences that separate those who will become addicted to alcohol from those who drink in moderation.
It took decades to craft the experiment, says study coauthor William Muir, a population geneticist at Purdue University in West Lafayette, Ind. Starting in the 1980s, rats bred at Indiana University School of Medicine in Indianapolis were given a choice to drink pure water or water mixed with 10 percent ethanol, about the same amount of alcohol as in a weak wine. For more than 40 generations, researchers selected rats from each generation that voluntarily drank the most alcohol and bred them to create a line of rats that consume the rat equivalent of 25 cans of beer a day. Simultaneously, the researchers also selected rats that drank the least alcohol and bred them to make a line of low-drinking rats. A concurrent breeding program produced another line of high-drinking and teetotaling rats.

For the new study, Muir and colleagues collected DNA from 10 rats from each of the high- and low-drinking lines. Comparing complete sets of genetic instructions from all the rats identified 930 genes that differ between the two lines.

Such a large number of genes, “shows how complex the genetic underpinnings of the drive to consume alcohol might be,” says Miles.

Often, human genetic studies known as genome-wide association studies, or GWAS, can’t determine which of many genes in a particular region of DNA is involved in a disease or addiction. But the Indiana researchers’ DNA data allowed them to pinpoint the exact genetic tweaks implicated in the rats’ drinking. “With GWAS, they’re just trying to get down to the gene — we’ve got it down to the parts of the genes,” Muir says.

That precision “is clearly an advance,” says John Crabbe, a neuroscientist at the Portland VA Medical Center in Oregon. “No one has gone into this much detail before in any alcohol-related trait.”
Most of the time, the genetic variant associated with drinking behavior wasn’t located within the part of the gene containing blueprints for a protein, the researchers discovered. Only four genes contained variants in their protein-producing parts. The majority of the differences were in surrounding DNA that regulates gene activity. Those changes could alter how much protein is produced from the genes, says study coauthor Feng Zhou, a neurobiologist at Indiana University School of Medicine. In turn, altering amounts of proteins could shift biochemical reactions important for determining behavior.

Until recently, scientists thought alcoholism and other problems stemmed from inheriting altered forms of genes that would produce faulty proteins. “Well, that game’s over,” says Crabbe. Now researchers realize that regulating gene activity is often just as important as changing the genes themselves.

The researchers don’t yet know whether the genes identified in the rats are the same ones that lead to drinking problems in people.