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The Promise and Peril of Genome-Wide Association Studies



Michael Boehnke, Ph.D., has spent two decades searching for the genetic roots of type 2 diabetes, which affects more than 300 million individuals worldwide and accounts for 10 percent of U.S. health care costs. “We’ve made real progress over the last 10 to 12 years, which has been true for a lot of common diseases. …Technology improvements have allowed us to do a much better job of scouring the genome to identify genes and variants associated with disease,” Boehnke told attendees of a University of Utah-sponsored conference on precision medicine.

Progress may seem slow. According to Boehnke, a professor of biostatistics and director for the Center of Statistical Genetics and the Genome Science Training Program at the University of Michigan, diabetes has been called the “geneticist’s nightmare.” A decade ago, only three genes were tied to the disease.

But today, we know of more than 100 common markers for type 2 diabetes and more than 60 for glucose intolerance and insulin resistance, said Boehnke, who believes the key to further discovery is collaboration. It’s the only way to get the large sample sizes needed to conduct population studies, including Genome-Wide Association studies, or GWAS.

The outcome of GWAS has not been what scientists expected. They perform as they should, identifying common genetic variations among large populations of people. For example, the T2D-GENES study, of which Boehnke is the principal investigator, is a large collaborative project focused on whole-exome sequencing in more than 10,000 people from five ethnicities, whole-genome sequencing of 600 Mexican-American individuals and transethnic meta-analysis.

The challenge with these studies, however, is that common variants, though partially responsible for diabetes, may not be the variants that deeply impact its course or have therapeutic potential.

But Boehnke believes the model of finding rare variants of large effect “really doesn’t fit” for type 2 diabetes. “It could be that by some miracle there is a very small fraction of the genome we’re not covering that’s just filled with high-effect genes for type 2 diabetes, but I don’t think that’s the case,” he states. More likely there are “many variants of modest effect.”

By: Daniela Liese

Daniela Liese is a medical writer for ARUP Laboratories