04:47am Wednesday 12 December 2018

Largest ever diabetes genetics study uncovers mechanisms behind type 2 diabetes

A study published in the journal Nature Genetics used genetic data from nearly a million people across Europe and North America to highlight some of the key ways in which type 2 diabetes develops, and to find several genes which could be attractive targets for the creation of new therapeutic drugs.

Together with colleagues from a global consortium of scientists, researchers from the Radcliffe Department of Medicine and the Wellcome Centre for Human Genetics at Oxford University analysed nearly 20 trillion data points to produce the most comprehensive catalogue so far of the places within the human genome where DNA sequence changes alter a person’s risk of developing Type 2 diabetes.

Diabetes occurs when the body’s ability to produce or respond to the hormone insulin is impaired, leading to elevated levels of glucose in the blood. Type 1 diabetes usually starts in childhood and is due to permanent loss of the beta cells in the pancreas that produce insulin. Type 2 diabetes typically develops later in life, and a person’s risk depends on the combination of genetic and lifestyle factors (such as diet and exercise, through their impact on a person’s weight).

The researchers used an approach called genome-wide association analysis, which involved scanning the complete set of DNA (the genome) from many people, to find if particular versions of the DNA sequence are more or less common in those with a particular illness. The researchers combined genetic data generated in 32 different studies, analysing the genomes of a total of 898,130 people (all of them of European descent).

The very large number of people included in the study meant that the researchers were able to find genes associated with diabetes which had been missed in previous studies, either because the consequences of the genetic changes for diabetes risk were subtle, or because the changes themselves were rare.

In all, the researchers found 400 spots in the human genome which were associated with Type 2 diabetes, doubling the previously known number.

They then zoomed into these regions to find the specific DNA changes that were responsible for the effects on diabetes risk. Many of these changes sit in parts of the genome that act as switches, turning on and off key genes in the insulin-producing pancreatic beta-cells.

The researchers also looked at how the combination of multiple diabetes-associated DNA changes affects diabetes risk for individuals, and found that people with the highest count of diabetes-associated sequence were nine times more likely to have diabetes than those with the lowest count.

Senior author Professor Mark McCarthy from the Oxford University Radcliffe Department of Medicine said: ‘These analyses do not yet indicate that knowing one’s own ‘genetic risk score’ will be of value to everyone, but it does highlight that there is a subset of people with very high genetic risk, and they might benefit from focused efforts to optimise their diet and fitness regimes.’

Lead author Dr Anubha Mahajan from the Wellcome Centre for Human Genetics said: ‘Understanding how these DNA changes lead to increased risk of diabetes also allows us to identify what may be targets for new ways of treating and preventing this condition: around 10% of the signals we found are in ‘coding’ regions of the genome that point directly to genes that can be potential therapeutic targets. What’s more, by looking at the impact of variations in the genome on heart disease as well as Type 2 diabetes, we’ve been able to find the most promising set of targets for further research.’

The results in this study are based on data from people with European heritage, but the researchers are currently pursuing similar analyses in people from other regions of the world.

‘These findings illustrate the kind of promising results we hoped for when we developed the Accelerating Medicines Partnership program,’ said Griffin P. Rodgers, M.D. M.A.C.P., director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). ‘As this research shows, sharing genomic data from studies around the world allows us to make unprecedented progress in understanding the genetic causes of type 2 diabetes.’

NIDDK is part of the U.S. National Institutes of Health. Major funders for the study were the Wellcome Trust and the US National Institutes of Health. For the full list of funders, please see the published paper.

The full paper, ‘Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps,’ can be read in Nature Genetics.

 

 


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