Genetic Sequencing Sheds Light on Diabetes Risk

Researchers gain insight on genetic variants that influence the development of type 2 diabetes.

A new study published in Nature provides a more complete picture of the genes responsible for type 2 diabetes, in particular previously identified common alleles.

While analyzing genes of individuals from 5 ethnic groups, researchers were also able to identify a novel variant that is specific to East Asians.

The analysis is the largest, multi-ethnic, genetic sequencing study published to date, and included more than 300 scientists from 22 countries, using DNA from 120,000 individuals. Participants had ancestral origins in Europe, South and East Asia, Africa, and the Americas.

“Our study has taken us to the most complete understanding yet of the genetic architecture of type 2 diabetes,” said co-senior study author Michael Boehnke. “With this in-depth analysis we have obtained a more complete picture of the number of characteristics of the genetic variants that influence type 2 diabetes risk.”

The collaboration combined 2 research projects, GoT2D and T2D-GENES. The researchers were able to identify more than a dozen genetic regions that harbor variants that influence the risk for type 2 diabetes. A majority of the variants were common and found in all human populations.

Furthermore, most of them had already been previously detected by other genome-wide association studies. The results of the study revealed an association between type 2 diabetes and a variant in the PAX4 gene, which is only present in people from East Asia, including China, Korea, and Singapore.

Additionally, researchers were able to demonstrate that variants in the gene TM6SF2, which has been previously linked to fatty liver disease, influences the risk of type 2 diabetes. Researchers completed whole genome sequencing of more than 2600 people and exome sequencing of 13,000, complemented with genome- or exome-wide array genotyping of 111,000 people.

“The study highlights both the challenges we face and the opportunities that exist in resolving the complex processes underlying a disease such as type 2 diabetes,” said researcher Mark McCarthy. “In this study, we have been able to highlight, with unprecedented precision, a number of genes directly involved in the development of type 2 diabetes. These represent promising avenues for efforts to design new ways to treat or prevent the disease.”

There has been an ongoing debate of whether genetic differences that influence predisposition to common diseases, such as diabetes, are widely shared within populations, or if they are more likely to be unique events that are specific to an individual and their family.

“While rare variants certainly influence type 2 diabetes risk, our results demonstrate that common variants shared across populations explain most of the genetic risk to type 2 diabetes,” Boehnke said.

Type 2 diabetes is the most common form of the disease, and is considered a major threat to global public health because of the rapid increase in diabetes-related deaths. In order to improve prevention and treatment for diseases, it is imperative to take each individual’s genetic makeup into account, concluded lead study author Christian Fuchsberger.

“Precision medicine relies on the deep understanding of the genetic architecture of a disease,” Fuchsberger said. “Our work provides this key information for type 2 diabetes.”

Although working towards precision medicine can be challenging, study authors noted that the findings will provide researchers with more knowledge and understanding of the disease.

“Our study tells us that most people are at risk for type 2 diabetes due to hundreds or even thousands of genetic variants, typically shared across populations,” said co-lead study author Jason Flannick. “While this large range of genetic risk may challenge our efforts at precision medicine, our consortium also offers a publicly accessible dataset, unprecedented in scope, for researchers around the world to advance our molecular understanding of type 2 diabetes.”