Study Looks at Genetic Components of Type 2 Diabetes

The largest-ever genetic comparison of people who do and do not have type 2 diabetes mellitus (T2DM) concludes that susceptibility to the disease stems from a large number of common genes rather than a small number of rare genes.

Investigators performed whole-gene sequencing on 2,657 Europeans and exome-wide sequencing on 12,940 people from Europe, South Asia, East Asia, Africa and the Americas. They then expanded the sample size with genome-wide or exome-wide genotype data from another 111,548 subjects.

The subsequent analysis of healthy and diabetic subjects — which was published in Nature — found hundreds of genes that play some role in disease development.

“Our study has taken us to the most complete understanding yet of the genetic architecture of type 2 diabetes,” said Michael Boehnke, the Richard G. Cornell Distinguished University Professor of Biostatistics, director of the Center for Statistical Genetics at the University of Michigan’s School of Public Health and one of 3 senior authors of the study. “With this in-depth analysis we have obtained a more complete picture of the number and characteristics of the genetic variants that influence type 2 diabetes risk.”

Prior research — mostly genome-wide association studies that compared truncated genetic information from large numbers of people — had already turned up most of the genetic variants identified by the new study. All told, however, those variants explained only a small fraction of disease risk, so it was possible that undiscovered genetic variants accounted for many (or even most) cases of the disease.

A number of researchers hypothesized that a handful of relatively rare genes were the likely catalysts of most T2DM. Carriers who failed to eat well and exercise would prove extremely likely develop the disease, they speculated, but others would face little threat from diabetes, no matter what their lifestyle choices.

The new study did identify a number of previously undiscovered genetic variants that increase diabetes risk — including some relatively rare ones — but it mostly affirms the results of the earlier association studies. A large number of common genes play a role in diabetes risk. A high percentage of the world’s population has enough of those genes to develop the disease. Genes alone usually are not enough to produce the disease, though. Lifestyle and environment play an even larger role than genetics in disease development for most patients.

The bad news that relatively few people are entirely safe from T2DM was somewhat offset by the good news that some diabetes-related genes may be good targets for new drugs.

"This 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 Mark McCarthy, the Robert Turner Professor of Diabetic Medicine and group head of the Wellcome Trust Centre for Human Genetics. "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.”