Search is on for Rarely Occurring Genetic Variants for Type 2 Diabetes

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“Missing heritability” has become the holy grail in the search for genetic variants underlying type 2 diabetes.

Genome-wide association studies have linked over 60 commonly occurring susceptibility loci to type 2 diabetes, but the impact of each of these variations is modest. These commonly occurring variants represent only about 10 percent of overall risk for developing the disease, said Mark McCarthy, MD, professor of diabetic medicine at the University of Oxford.

McCarthy is one of the leaders of an international research consortium with a unique approach to identifying missing heritability, that is, the genetic variants that rarely occur in the population but that may have much stronger effects on type 2 diabetes disease risk than do the common variants thus far identified.

The consortium’s approach is to sequence and analyze the whole exomes—or coding portions of genes—of 10,000 individuals of five major ancestry groups: African American, East Asian, European, Hispanic, and South Asian.

The search for the variants that influence an individual’s genetic predisposition for developing type 2 diabetes and renal disease requires such large population studies and often many years of work, said Arlene Chapman, MD, professor of medicine at Emory University. “This research has to be conducted in various stages and must be replicated,” she said.

Including patients and controls representing the major ancestry groups strengthens the likelihood that variants may be discovered that either characterize all ancestries or just one group, said Chapman. Variants may include those that reduce risk and thereby are protective as well as those that increase risk for developing the disease, she said.

Genomics studies in the past have focused on individuals of Northern European ancestry, said leading genomics researcher Nicholas Katsanis, PhD. However, the variants identified in any one group “may be invisible in other populations,” he said. Katsanis is the Jean and George Brumley Jr., MD, professor of developmental biology, and professor of pediatrics and cell biology at Duke University.

Because each ancestry group in the whole-exome studies includes equal numbers of controls and patients with type 2 diabetes, the researchers should be able to determine whether there are variants that increase or reduce an individual’s predisposition for developing diabetes, said Tanya M. Teslovich, PhD, who spoke about the research at a recent meeting of the American Society of Human Genetics in San Francisco.

Teslovich, a research fellow in statistical genetics at the University of Michigan, and McCarthy are among the 75 scientists at 27 universities and other institutions participating in the Type 2 Diabetes—GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) collaboration.

Although the commonly occurring loci already identified by genome-wide sequencing confer only a moderate risk, Teslovich and the other researchers regard them as beacons.

“We hypothesize that genes underlying the common signals identified in genome-wide sequencing also harbor low-frequency and rare variants,” she said.

“Screening the exomes in a range of diverse ethnic groups increases the range of variants of each gene surveyed, and thereby improves our ability to detect genes showing differences in the patterns of the DNA codes for proteins between individuals with type 2 diabetes and controls,” Teslovich said.

Initial analysis of the sequence data of 3500 African American, East Asian, and South Asian individuals identified about 1.6 million single nucleotide variants (SNVs), 71.5 percent of which were previously unknown.

“Only about 89,000, or 5.6 percent, of these 1.6 million variants are present in all three ancestry groups,” she said.

About 35.4 percent of the SNVs are unique to African Americans, while 35.4 percent and 30.6 percent, respectively, occur only in East Asians and South Asians. The analysis is too preliminary to state that these population-specific variants are associated with type 2 diabetes and contribute to disease risk in a single population, Teslovich said.

During the analysis of the sequence data on the participants with East Asian ancestry, Teslovich and her colleagues found that a variant in the PAX4 gene is associated with type 2 diabetes. Previous studies have shown that the gene is involved in pancreatic islet development and is linked to early diabetes onset.

In early 2013, the researchers will complete the exome sequencing of the 10,000 individuals in the study population. About 5300 individuals, half with type 2 diabetes and half controls, have been sequenced thus far, Teslovich said.

The study’s design should yield a catalog of variations, including alleles that are common in the general population as well as those that are observed in only a small number of individuals.

“We will then examine each of the variants to determine which ones may affect an individual’s risk of developing type 2 diabetes,” she said.

Even if the Type 2 Diabetes—GENES collaboration does not identify any rarely occurring variants with a strong effect on risk for type 2 diabetes, the group’s findings will add to researchers’ and clinicians’ knowledge of diabetes.

“To some extent that doesn’t matter because we can still learn a lot about the biology of diabetes from such variants, and that has always been our primary motivation,” McCarthy said.

February 2013 (Vol. 5, Number 2)