Genetics of type-2 diabetes revealed in unprecedented detail

More than 300 scientists from 22 countries collaborated on the study, which analyses the genomes of more than 120,000 people with ancestral origins in Europe, South and East Asia, the Americas and Africa. Niels Grarup, Oluf Pedersen and Torben Hansen alongside other researchers from the Metabolism Centre at the University of Copenhagen, the Research Centre for Prevention and Health in Glostrup, Vejle Hospital, Steno Diabetes and Aarhus University, contributed to the study.

The findings, published in the scientific journal, Nature, identify several new genes related to diabetes, which could potentially be used to develop new diabetes treatments. The findings also reveal the high level of complexity of the genetics behind type-2 diabetes (T2D), a fact that must be addressed by way of 'more personalised strategies in terms of both treatment and prevention', according to Niels Grarup.

T2D is a growing threat to global health. More than 300,000 Danes are diagnosed with T2D and more than 500,000 have unrecognized T2D or pre-diabetes. T2D is a complex disease, resulting from an unfortunate interaction between genes and environment.

A better understanding of which precise genes prevent or contribute to the development of T2D would enable researchers to develop new ways of treating and preventing this condition while also offering the prospect of targeting the treatments towards those most likely to benefit and those least likely to suffer side effects.

Previous studies have identified 80 areas in the genome associated with T2D. These studies focused on the most prevalent DNA variations. Each identified variation contributes only modestly to the risk of developing T2D and as yet, the underlying diseases mechanisms in most variants are still unknown.

This new study contributes a highly detailed investigation of low-frequency variants (1-5% frequency) and rare variants (<1% frequency) in healthy individuals and T2D patients. The study comprises whole genome sequencing of 2,600 individuals, whole exome sequencing of 13,000 individuals and exome chip-genotyping of 111,000 individuals (the exome is the protein-coding part of a genome).

Researchers compared the genetic variation in individuals with T2D and individuals without T2D, which in turn enabled them to test the importance of the rare “personal” DNA-variations specific to the development of T2D.

They found that most of the genetic risk connected to T2D can be attributed to the more common and widespread variations in the genetic code, i.e. the variants with a frequency below 5%. “Some rare variants are most certainly decisive to the development of T2D, however, the findings in this study reveal that many common risk T2D variants are shared across populations.

The researches identified more than a dozen risk genes related to T2D, where changes in the DNA sequences altered the composition of the proteins they encode.

One such variant – in the TM6SF2 gene – which has been be shown to alter the amount of fat stored in the liver, also increases the risk of developing T2D.

Mark McCarthy, from the Wellcome Trust Centre for Human Genetics at the University of Oxford, one of three senior authors of 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 T2D. In this study, we have been able to highlight, with unprecedented precision, a number of genes directly involved in the development of T2D. 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 T2D. With this in-depth analysis we have obtained a more complete picture of the number and characteristics of the genetic variants that influence T2D risk.”