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Combined GWAS, Protein Network Analysis Reveals Genes Contributing to Alcohol Dependence

NEW YORK (GenomeWeb News) – A new genome-wide association and protein network analysis study has identified more than three-dozen genes that appear to be involved in the risk of developing alcohol dependence.

As they reported online yesterday in the American Journal of Human Genetics, researchers from Yale University, the University of Iowa, and elsewhere assessed GWAS data for thousands of individuals with or without alcohol dependence. Rather than relying solely on SNP data, though, they also added in an analysis of interactions between proteins encoded by genes containing possible risk variants.

Using that approach, the team unearthed a 39-gene network associated with alcohol dependence in the discovery cohort and in additional case-control groups representing European-American and African-American individuals. And a more detailed dive into the network is expected to help in understanding factors contributing to alcohol dependence as well as the biology behind the condition.

"The proteins made by these genes could be neighbors, or they could be part of the same functional biological pathway," the study's first author Shizhong Han, a psychiatry researcher with the University of Iowa's Carver College of Medicine, said in a statement.

"We took advantage of their biological relatedness to identify a network of genes that interact and together contribute to the susceptibility to alcoholism," Han said.

Though some risk factors for alcohol dependence were previously detected using linkage and candidate gene studies, Han and colleagues noted, GWAS-based efforts to more fully define inherited contributors to the condition have been hindered by relatively weak signals and/or findings that aren't corroborated by follow-up studies.

For their part, the study authors reasoned that "[m]ore sophisticated analyses of existing GWAS data, rather than SNP-level analysis, has the potential to enhance the identification of true genetic signals, enhance our understanding of its biological underpinnings, and contribute to the development of innovative diagnostic and therapeutic strategies."

To that end, the team turned to genotyping data for 1,453 cases and 1,217 controls from the European-American population and 708 cases and 442 controls from the African-American population. The participants had been enrolled through two large efforts: the Collaborative Study on the Genetics of Alcoholism project and the Study of Addiction: Genetics and Environment project.

With the GWAS data alone, researchers picked up variants with tenuous ties to alcohol dependence, including SNPs with suggestive associations in either European Americans or African Americans that did not replicate in the other population.

But by folding in protein-protein interaction modules developed using data from the Human Protein Interaction Network, they were able to track down a set of 39 interacting genes in seven protein network modules that contained a higher-than-usual representation of potential risk SNPs.

The association between the network genes and alcohol dependence held true not only in the discovery group, but also in three additional cohorts — two containing European-American cases and controls and a third representing African-American individuals, researchers reported. Moreover, the set of 39 genes included several candidates from past genetic studies of alcohol dependence.

On the other hand, the team did not pick up significant associations between the newly detected gene network and other complex conditions such as bipolar disorder, depression, and diabetes.

By delving into the nature of the genes involved in the alcohol dependence-associated network, the study's authors are optimistic about the possibility of better understanding and perhaps treating the condition. They noted, for example, that the network contains higher-than-usual representation by genes coding for proteins involved in ion transport, synaptic function, and nerve transmission pathways.

"The discovery of these genes may open a new window into the biological mechanisms underlying this alcoholism disorder," Han said in a statement. "Eventually, it's our hope that the findings might help to develop drugs to treat or prevent this disorder."

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