Ten new diabetes gene links offer picture of biology underlying disease

The study provides a fuller picture of the genetics and biological processes underlying type 2 diabetes, with some clear patterns emerging.

The international team, led by researchers from the University of Oxford, the Broad Institute of Harvard and MIT, and the University of Michigan, Ann Arbor, used a new DNA chip to probe deeper into the genetic variations that commonly occur in our DNA and which may have some connection to type 2 diabetes.

Their findings are published in the journal Nature Genetics.

'The ten gene regions we have shown to be associated with type 2 diabetes are taking us nearer a biological understanding of the disease,' says principal investigator Professor Mark McCarthy of the Wellcome Trust Centre for Human Genetics at the University of Oxford. 'It is hard to come up with new drugs for diabetes without first having an understanding of which biological processes in the body to target. This work is taking us closer to that goal.'

Approximately 2.9 million people are affected by diabetes in the UK, and there are thought to be perhaps a further 850,000 people with undiagnosed diabetes. Left untreated, diabetes can cause many different health problems including heart disease, stroke, nerve damage and blindness. Even a mildly raised glucose level can have damaging effects in the long-term.

Type 2 diabetes is by far the most common form of the disease. In the UK, about 90% of all adults with diabetes have type 2 diabetes. It occurs when the body does not produce enough insulin to control the level of glucose in the blood, and when the body no longer reacts effectively to the insulin that is produced.

The researchers analysed DNA from almost 35,000 people with type 2 diabetes and approximately 115,000 people without, identifying 10 new gene regions where DNA changes could be reliably linked to risk of the disease. Two of these showed different effects in men and women, one linked to greater diabetes risk in men and the other in women.

With over 60 genes and gene regions now linked to type 2 diabetes, the researchers were able to find patterns in the types of genes implicated in the disease. Although each individual gene variant has only a small influence on people's overall risk of diabetes, the types of genes involved are giving new insight into the biology behind diabetes.

Professor Mark McCarthy says: 'By looking at all 60 or so gene regions together we can look for signatures of the type of genes that influence the risk of type 2 diabetes.

'We see genes involved in controlling the process of cell growth, division and aging, particularly those that are active in the pancreas where insulin is produced. We see genes involved in pathways through which the body's fat cells can influence biological processes elsewhere in the body. And we see a set of transcription factor genes -- genes that help control what other genes are active.'

While gene association studies have been successful in finding DNA regions that can be reliably linked to type 2 diabetes, it can be hard to tie down which gene and what exact DNA change is responsible.

Professor McCarthy and colleagues' next step is to get complete information about genetic changes driving type 2 diabetes by sequencing people's DNA in full.

He is currently leading a study from Oxford University that, with collaborators in the US and Europe, has sequenced the entire genomes of 1400 people with diabetes and 1400 people without. First results will be available next year.

'Now we have the ability to do a complete job, capturing all genetic variation linked to type 2 diabetes,' says Professor McCarthy, a Wellcome Trust Senior Investigator. 'Not only will we be able to look for signals we've so far missed, but we will also be able to pinpoint which individual DNA change is responsible. These genome sequencing studies will really help us push forward towards a more complete biological understanding of diabetes.'

Professor McCarthy says: 'We now have strong evidence that there is a long tail of further common gene variations beyond those we have identified so far. The 60 or so we know about will be the gene variants with strongest effects on risk of type 2 diabetes. But there are likely to be tens, hundreds, possibly even thousands more genes having smaller and smaller influences on development of the condition.'

Notes

*It is possible to see how some types of genes identified in these studies could be involved in type 2 diabetes.

For example, one feature of type 2 diabetes is that the insulin-producing cells in the pancreas can no longer produce enough of the hormone to control glucose levels in the blood. However, it is not known whether this is because there are fewer cells left to respond to the demand, or there are plenty of cells but they don't respond as much, or both. Cell cycle genes, which control the growth, development and death of cells, could well play a role here.

Obesity is known to be a major risk factor for diabetes. Becoming obese tends to result in the body becoming less responsive to the insulin it produces. While fat must be important in this, it is the liver and muscle where the insulin resistance has an effect. The involvement of processes where fat cells communicate with other parts of the body, as suggested by the genetics findings, could explain how this occurs.

* The researchers show that the data emerging from gene association studies is consistent with the genetic contribution to diabetes being made up of many, many common gene variants each having a small effect. This is more likely than there being a significant contribution from unknown rare genetic variants that only a few people have, but which confer a much greater risk of diabetes.