New genetic variants involved in common diseases 02/08/07. By Chrissie Giles The Wellcome Trust Case Control Consortium publishes its findings on the genetic basis of a number of key diseases.

Since his mid-teens, Paul's life has been controlled by crippling abdominal pains, bouts of diarrhoea and rectal bleeding, and fevers, joint pain and skin rashes. As a result, Paul misses many days from work and finds it hard to be spontaneous in his social life. He also has to be extremely careful about what he eats and drinks.

Now in his late 20s, Paul has just undergone major abdominal surgery to remove his colon. While waiting for his wounds to heal sufficiently for the next operation (to rejoin his digestive tract), Paul has to use a pouch on the outside of the body, called a stoma, to collect intestinal waste.

Paul's situation is not unique: he's just one of the estimated 30 000 to 60 000 people in the UK who live with the pain, inconvenience and often embarrassing symptoms characteristic of Crohn's disease. Although surgery only stops symptoms rather than curing the underlying disease, some 80 per cent of affected people eventually undergo this procedure.

Despite much research, the basis of Crohn's disease is still unclear – why, for example, do most people live healthily with 'normal' gut bacteria, but others develop inflammatory bowel disease because of it?

Now though, new clues to the origins of Crohn's disease – and six other common conditions – have emerged from a landmark genetic study called the Wellcome Trust Case Control Consortium (WTCCC), a collaboration between 50 research groups with 200 scientists from dozens of UK institutions.

The £9 million project – the largest of its kind to date – was launched in 2005 to improve our understanding of the genetic basis of human disease. "It has been known for a long time that genetics plays a role in common human diseases," says Professor Peter Donnelly, Chairman of the WTCCC. "But what hasn't been clear is exactly which bits of the genome have an effect."

Funding the Consortium was a logical step for the Wellcome Trust, which supported the Human Genome Project, the SNP (single nucleotide polymorphism) Consortium – a search for common genetic variants that occur at single nucleotides (bases) in the DNA sequence – and the International HapMap Project, which examined how groups of SNPs are inherited in blocks. "The next step was to look at these SNPs in the context of human disease," says Dr Mark Walport, Director of the Trust.

Looking across the genome

Case–control studies are widely used to pinpoint the genetic and environmental factors that may contribute to disease. Two groups of participants are involved: 'cases', people who have a particular disease, and 'controls', healthy people without the disease.

But the WTCCC was no standard case–control study, because it involved genetics at a scale not seen before. Researchers examined the whole genome for variants, looking at some half a million SNPs in the DNA of 17 000 people – 2000 people with each of seven different diseases and 3000 healthy controls. The scale is significant because many genes are likely to influence susceptibility to common diseases such as diabetes and Crohn's disease, but the effect of individual genes is small. Only by looking at thousands of people can researchers tease apart subtle genetic effects from the 'background noise' of normal genetic variation.

Professor Donnelly explains that while certain genetic approaches were initially successful in investigating the basis of disease, they hadn't lived up to researchers' hopes. So-called genome-wide association studies, however, have proved extremely valuable in the WTCCC and hold great hope for the future. "If you think of the genome as a dark, long road, we were previously able to turn lights on in a small number of places," he says. "What's new is the ability to 'turn on' half a million lights and to 'see' a large proportion of the variation there."

As well as identifying parts of the genome that potentially influence a person's susceptibility to or protection from certain diseases (see box), the data generated have also hinted at previously unknown links between some conditions.

One of the most exciting and unexpected of these links is the discovery that variants in a gene called PTPN2 are common both in people with type 1 diabetes and in people with Crohn's disease. "Type 1 diabetes is well know to be associated with rheumatoid arthritis, autoimmune thyroid disease and other immune disorders," explains Professor John Todd, a Principal Investigator in the WTCCC from the University of Cambridge. "But no one suspected a link with Crohn's disease."

The researchers identified two other genes and one genetic region involved in Crohn's disease, one of which is involved in a pathway called autophagy ('self-eating'), which is crucial for clearing bacteria from cells. The involvement of this pathway was a complete surprise, but has provided a major lead in terms of possible new treatments.

"We know some drugs that affect the autophagy pathway, so we can start to study these drugs in patients with Crohn's disease," says Dr Miles Parkes, a WTCCC Principal Investigator from Addenbrooke's Hospital and the University of Cambridge.

In addition, two of the variants associated with Crohn's disease are in 'gene deserts', areas of the genome with few if any genes. It's thought that these areas can influence disease states by affecting genes elsewhere in the genome. "It's the entire genome and genotype that counts," says Professor Todd. "That's why genome-wide studies are so important and so informative."

Apart from their potential in directing future treatments, what do these results mean for us? Well, it's important to remember that genetic factors are only one part of the story for common diseases.

As expected, multiple genes are involved in these diseases and the variants of any one gene typically increase the risk of getting the disease by 20–50 per cent, compared with the general population. In some of the more extreme cases, having two copies of a 'disease' variant doubles the risk of getting the disease in question. In terms of heart disease, this effect is about the same as that of having high cholesterol.

But these data aren't about predicting who will suffer from a disease and who will not, they're more about understanding the risk factors involved in a particular disease. "People might ask, 'have I got the diabetes gene?' But it's not as simple as that," says Professor Todd. "It's about hundreds of genes contributing to a threshold of genetic susceptibility that might – in the right environment – push you over the edge to disease."

The initial success of the WTCCC bodes well for future genome-wide studies, and in July 2007 the Trust announced funding for the genotyping of DNA samples from other disease collections or cohorts. Furthermore, the WTCCC was awarded a further £7.7m to investigate in detail the genes it had identified.

"We're just scratching the surface," says Professor Donnelly. "If you'd asked last autumn how many genes were known to be associated with the seven common diseases we've examined, the answer would be about ten. Today, the answer's probably around 30, and this figure should grow very substantially in the future."

Chrissie Giles is a writer at the Wellcome Trust.