More than 300 scientists from 22 countries collaborated on the study, which analysed the genomes of more than 120,000 people with ancestral origins in Europe, South and East Asia, the Americas and Africa.
The findings, published today in Nature, identify several potential targets for new diabetes treatments, but also reveal the complexity of the disease that needs to be addressed by efforts to develop more personalised strategies for treatment and prevention.
Type 2 diabetes is a growing threat to global health, with one in 10 people either having the disease or predicted to develop it during their lifetime. For any given individual, the risk of developing this form of diabetes is influenced by the pattern of genetic changes inherited from their parents, and environmental factors such as levels of exercise and choice of diet.
A better understanding of precisely how these factors contribute to type 2 diabetes will enable researchers to develop new ways of treating and preventing this condition, as well as offering the prospect for targeting those treatments towards those most likely to benefit, and those least likely to suffer harm.
Previous studies have identified over 80 areas in the genome that are associated with type 2 diabetes. However, these studies focused on the role of common DNA differences that appear frequently in the population, and they generally stopped short of identifying exactly which DNA sequence changes, or which specific genes, were responsible for this risk.
Today's study explored the impact of changes in the DNA sequence on diabetes risk at a more detailed level. Some individuals had their entire genome sequenced while for others, sequencing was restricted to the part of the genome that codes directly for proteins (the exome).
Scientists compared the genetic variation between individuals who had type 2 diabetes and those who did not. This allowed them to test the contribution made by rare, 'private' DNA differences, as well as those that are common and shared between people.
They found that most of the genetic risk of type 2 diabetes can be attributed to common, shared differences in the genetic code, each of which contributes a small amount to an individual's risk of disease. Some researchers had thought that genetic risk would instead be dominated by rare changes, unique to an individual and their relatives.
This finding means that future efforts to develop a personalised approach to treatment and prevention will need to be tailored toward an individual's broader genetic profile, non-genetic risk factors and clinical features.
Researchers also identified over a dozen type 2 diabetes risk genes where the DNA sequence changes altered the composition of the proteins they encode. This implicates those specific genes and proteins directly in the development of type 2 diabetes.
One such variant – in the TM6SF2 gene – has been shown to alter the amount of fat stored in the liver, which in turn results in an increase in the risk of type 2 diabetes. Discoveries such as these point to new opportunities for developing drugs that might interrupt the development of the disease.
Mark McCarthy, from the Wellcome Trust Centre for Human Genetics at the University of Oxford, one of three senior authors on the paper, said: "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. 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."
Joint senior author Professor Michael Boehnke, Richard G Cornell Distinguished University Professor of Biostatistics, Director, Center for Statistical Genetics, University of Michigan School of Public Health, added: "Our study has taken us to the most complete understanding yet of the genetic architecture of type 2 diabetes. 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."
Data and discoveries generated through this project are available through the type 2 diabetes genetics portal (www.type2diabetesgenetics.org) developed as part of the Accelerating Medicines Partnership.
Jason Flannick, co-lead author and Senior Group Leader at the Broad Institute of Harvard and MIT and Research Associate at the Massachusetts General Hospital, said: "Our study tells us that genetic risk for type 2 diabetes reflects hundreds or even thousands of different genetic variants, most of them shared across populations. This large range of genetic effects may challenge efforts to deliver personalised (or precision) medicine. However, to ensure that these challenges can be taken up by the wider research community, we have made the data from our study publicly accessible for researchers around the world in the hope that this will accelerate efforts to understand, prevent and treat this condition."
This research was funded by over 60 funders including the Wellcome Trust, the US National Institutes of Health, the UK Medical Research Council, and the European Commission.