A genome-wide study into the genetic roots of alcohol dependence has identified several areas of DNA that appear to contribute to alcoholism. But the researchers say those genes make relatively modest contributions to overall risk of the disease.
The genome-wide study is one of the first to be published as part of the Genes, Environment and Health Initiative (GEI), a $48 million project funded by the National Institutes of Health. It is available online in the Proceedings of the National Academy of Sciences Early Edition.
“We didn’t identify an alcoholism gene, but I believe these findings eventually will help us learn more about the genetic architecture underlying a complex illness like alcoholism,” says principal investigator Laura Jean Bierut, M.D., professor of psychiatry at Washington University School of Medicine in St. Louis.
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Bierut heads the national GEI study of addiction, looking both at genetic and environmental factors related to substance use, abuse and dependence. For this project, Bierut’s team focused on only one addictive substance: alcohol.
Bierut
The investigators looked at DNA from 1,897 alcoholics and 1,937 people who drank but were not alcohol dependent. Those individuals were part of the Study of Addiction: Genetics and Environment (SAGE). Analyzing the SAGE data yielded 15 areas of DNA called single nucleotide polymorphisms (SNPs) that appeared linked to alcoholism.
But when the researchers went back and looked at DNA from almost 4,000 people in two other datasets, Bierut’s team could not identify any statistically significant association between the SNPs found in the SAGE study and risk for alcohol dependence.
“Admittedly, we had a rather conservative statistical model, and some of these DNA regions may have a modest influence on alcohol dependence,” Bierut says. “But none of the top 15 genetic influences from the SAGE study were replicated in the data from other studies. The fact that the findings didn’t replicate between the datasets doesn’t mean that these DNA regions are not involved. We may just have only one small piece of the story.”
In addition to the genome-wide scans, the researchers also looked at a particular gene that has proven to be significant in other genetic studies of alcoholism.
That genetic target is GABRA2, a gene involved in regulating nervous system activity. This study shows GABRA2 is statistically relevant in both the SAGE study and in the other large samples, but again, its contribution to alcoholism appears to be rather small.
“We found that the GABA receptor gene did have an effect,” Bierut says. “But although its influence is among the strongest we’ve identified, the effect still is very modest.”
She says, however, that many psychiatric illnesses involve multiple genes that have modest effects. These findings suggest that alcoholism works the same way.
In fact, several other genome-wide association studies have had little luck in identifying genetic variants that contribute to common diseases. Many of the SNPs that have been isolated in these studies actually explain only small portions of disease risk. Bierut says, however, that looking both at genes and at environmental factors should eventually allow scientists to better understand the risks for behavior disorders such as alcoholism.
Bierut and the other investigators have shared the data from their studies on Genotype and Phenotype (dbGaP). The Web site (ncbi.nlm.nih.gov/gap) is sponsored by NIH.
“The information has been available not only to our investigative team but to the entire scientific community,” Bierut says.
From here, she says it will be important to untangle other genetic and environmental influences, and to better define subtypes of alcoholism that may be more related to some of these genes.
“This type of study simply reinforces the notion that there is a great deal of genetic complexity that underlies human behavior,” she says.
Bierut LJ, Agrawal A, Bucholz KK, et al. A genome-wide association study of alcohol dependence. PNAS Early Edition, March 1, 2010.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.