A group of researchers have recently identified several DNA alterations that are linked to type 2 diabetes. Analyzing coding genes from almost 46,000 individuals, the study was one of the largest sequencing studies of its kind conducted to date, and included data from European, African American, East and South Asian, and Hispanic/Latino people. The work was published this week in the journal Nature.
This pool of data included about 21,000 patients with type 2 diabetes and 25,000 healthy individuals. Comparing their genomes, the researchers identified four genes that contained rare genetic deviations that were associated with diabetes. These genes and the proteins that they code for could become targets for new medications and may help researchers better treat the condition. The portion of the genome analyzed in this study included only the DNA that codes for proteins, known as the exome.
“These results demonstrate the importance of studying large samples of individuals from a wide range of ancestries,” said the study’s senior author Michael Boehnke, professor of biostatistics and director of the Center for Statistical Genetics 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.”
The World Health Organization estimates that over 400 million people globally are living with diabetes, with most of these cases being type 2 diabetes. The disease is one of the leading causes of death globally, and managing the condition poses a challenging and tedious task for patients. Scientists have uncovered many lifestyle and dietary factors that play into the disease, but recent advancements have put emphasis on sequencing genomes to gain a better understanding of molecular components tied to diabetes.
As opposed to only analyzing the exome, another way to research genetic variants in diseases is the genome wide association study, in which the entire genome is analyzed. This approach is effective in finding the common variants in the genome but can often miss the rare exome variants. Though these variants are often difficult to find, they hold great importance in identifying new targets for pharmaceutical agents.
“We now have an updated picture of the role of rare DNA variations in diabetes,” said first author Jason Flannick, assistant professor of pediatrics at Harvard Medical School and the Division of Genetics and Genomics at Boston Children’s Hospital. “These rare variants potentially provide a much more valuable resource for drug development than previously thought. 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.” Flannick is also an associate member of the Broad Institute of MIT and Harvard.
Researchers strive to have the largest sample size possible in their studies, and with a population size well over 40,000, this could potentially be the largest exome study of type 2 diabetes conducted. The researchers noted that though their population size was massive, they may need somewhere between 75,000 and 185,000 cases to identify the rarest variants that impact the disease.
“It’s critical to remember that just because we are examining variants in protein-coding DNA, we don’t get a break on the number of samples needed to detect a significant effect,” explained Jose Florez, chief of the endocrine division and diabetes unit at Massachusetts General Hospital, professor of medicine at Harvard Medical School, and director of the diabetes research group at the Broad Institute. “The effects of these variations can be powerful, but because they are so rare, we still need to increase the sample size in order to really derive compelling insights.”
These findings can be found online via the Type 2 Diabetes Knowledge Portal, which provides researchers with access to prior findings for their own reference.
Exome sequencing in #T2D #diabetes of more than 44K cases and controls: new insights, new protective variants, drug targets, small impact of rare variants, but we need perhaps ~185K to learn more https://t.co/JAUOMJm4qB #openaccess @Nature pic.twitter.com/rXnA8f1IZ7
— Eric Topol (@EricTopol) May 22, 2019