DNA Alterations Linked to T2D in Large Cohort Study

With a cohort of approximately 50,000, this may be the largest exome sequencing study of type 2 diabetes.

An international consortium of scientists, through the Broad Institute of MIT and Harvard, has linked rare DNA alterations to type 2 diabetes through an analysis of protein-coding genes. These variants may provide a much more valuable resource for drug development than previously thought, according to Jason Flannick, first author on the study.

The study included a large cohort of approximately 21,000 individuals with type 2 diabetes, and 25,000 healthy controls. Participants included individuals with African American, East Asian, European, Hispanic/Latino, and South Asian ancestry.

Using the data from these participants, investigators sequenced the “exome,” or only those regions in the genome that code for proteins. They also performed single-variant association analysis for a subset of the sample using genome-wide arrays and imputation.

Investigators identified 4 genes with rare variants that affect diabetes risk and suggests that hundreds more genes may affect diabetes risk. The consortium then created a website, www.type2diabetesgenetics.org, to enable scientists to access the results of the study on an international scale.

Due to rare exome variants being extremely difficult to detect but also incredibly valuable for their insight into disease-related genes, investigators aim to increase sample sizes for their next study. With a cohort of approximately 50,000, this may be the largest exome sequencing study of type 2 diabetes; however, sample sizes ranging between 75,000 and 185,000 cases may be needed to identify even those rare variants with the largest impact.

"These results demonstrate the importance of studying large samples of individuals from a wide range of ancestries," said senior study author Michael Boehnke, professor of biostatistics at the University of Michigan School of Public Health. "Most large population studies focus on individuals of European ancestry, and that can make it hard to generalize the results globally. The more diverse the cohort makes for better, more informative science."

"We now have an updated picture of the role of rare DNA variations in diabetes," said Flannick, in a prepared statement. "We can actually detect evidence of their disease association in many genes that could be targeted by new medications or studied to understand the fundamental processes underlying disease,” said Flannick.

Reference

Massive sequencing study links rare DNA alterations to type 2 diabetes [press release]. Published May 22, 2019. https://www.sciencedaily.com/releases/2019/05/190522141758.htm. Accessed May 22, 2019.