Study finds youth-onset diabetes is a genetically distinct form of the disorder

The diabetes field has long classified the disorder into genetically distinct groups, including type 1 and type 2. However, new genetics research focused on a form of type 2 diabetes (T2D) that is becoming more common in adolescents suggests a more complicated picture. 
 
Researchers at the Broad Institute of MIT and Harvard, Boston Children's Hospital, and Harvard Medical School analyzed DNA from more than 3,000 T2D participants between 12 and 18-years-old and nearly 9,800 adult controls, more than three-quarters of whom were of African American or Hispanic ancestry. They found that youth-onset T2D is a genetically intermediate form of the disorder that lies on a spectrum between adult-onset T2D and rare forms of the disorder caused by a single gene.  

Adult-onset T2D is influenced by thousands of common genetic variants, whereas the rare genetic forms, known as monogenic diabetes, are caused by a single variant. However, in a recent Nature Metabolism paper, the researchers showed that youth-onset T2D shared some of the same genetic features as both forms, carrying both common and rare genetic variants. Moreover, these individuals harbored more of these variants than people with adult-onset T2D, suggesting that genetics has a larger role in causing youth-onset T2D than in the adult-onset form.

Flagging risk factors

Disease-causing genetic variants are generally classified as common (appearing in more than 5 percent in the population), rare (less than 1 to 5 percent of population), or monogenic (which are able to cause disease on their own). Teasing apart the contributions of these different types of variants in youth-onset T2D risk requires genetic data from thousands of patients.

To access such a large dataset, Kwak and Flannick turned to ProDiGY (Progress in Diabetes Genetics in Youth), a National Institutes of Health-funded research consortium that has sequenced the exomes (the protein-coding region of the genome) of thousands of adolescents with T2D and also collected common genetic variant data from many thousands of healthy adults.

Their analyses demonstrated that the combination of common and rare genetic variants in youth-onset T2D have a greater influence on disease risk than in the adult-onset form. Youth-onset patients' common variant risk was three-fold higher, and their rare variant risk was five-fold higher. 

Kwak and Flannick, building upon work previously published by the ProDiGY consortium, also found that 2.4 percent of the youth-onset T2D patients had monogenic diabetes, including a significant number of patients who carried variants in MC4R, a gene strongly linked to monogenic obesity. They said that these cases should be screened for monogenic diabetes, which might change the types of treatments they would receive.

“There’s a nontrivial fraction that is worth getting screened for monogenic forms of diabetes, even if they don’t exactly look like what typical monogenic cases look like,” said Flannick.

Towards precision medicine

Researchers have long thought that common variants are the most significant genetic risk factor for diabetes, but Kwak says that the study may change that thinking. “There’s been a long debate on the genetic architecture for T2D, and the field tends to lean toward the common variant hypothesis. But we show that there are rare variants that are important even after excluding the monogenic diabetes cases.”

Kwak and Flannick hope that their study can inform the development of new diabetes treatments and add that their approach can be used to better understand the genetic causes of other diseases.

“I think this could have a huge impact on other studies of complex disease with early-onset forms,” said Kwak. “There’s a lot of heterogeneity in the different forms of common disease. With this model, we can understand other conditions' genetic architecture.”