Common variants, common disease

When the originators of the Wellcome Trust Case Control Consortium (WTCCC) got together back in 2004 with a notion to analyse the power of genome-wide association studies, the plan was not necessarily to uncover new genes for diseases. The main game was always to find out whether this sort of huge study was actually feasible.

There were doubters, of course. As one of its principal investigators, Professor Matthew Brown, puts it, even 12 months ago some thought the whole venture was going to fall flat on its face.

"It was mainly for theoretical reasons," Brown, head of the musculoskeletal genetics group at the University of Queensland's new Diamantina Institute for Cancer, Immunology and Metabolic Medicine and one of the principal investigators of the study, says.

"One issue was size - people didn't think we could pull it off," Brown says. "Another one was that people thought that the genetic diversity between areas of the UK would be too great and would swamp any signal that we got from the diseases.

"And the third possibility was that people didn't know if, when you took a particular gene that was involved in disease, whether there was a single variant of that gene that predisposed to disease, in which case this study would pick it up, or whether there were lots of variants, in which case we would miss it. But clearly it has worked."

Overwhelmingly, it seems. The first study in the project, published in Nature in June, was a genome-wide association study of 14,000 cases with 3000 controls looking at seven common diseases. It confirmed 24 independent association signals and identified a further 58 that the authors believe is likely to infer additional susceptibility.

Of the 24 associations, one was identified in bipolar disorder, one in coronary heart disease, nine in Crohn's disease, three in rheumatoid arthritis, seven in type 1 diabetes and three in type 2 diabetes. According to the consortium, the study represents a thorough validation of the GWA approach.

The consortium also plans to publish two more studies shortly: one looking at TB in a west African population and another GWA study focusing on breast cancer, multiple sclerosis, ankylosing spondylitis and autoimmune thyroid disease.

Brown was involved from the onset of the study, helping with the design, analysis and with obtaining funding. He believes that the study has been a huge success and would like to see a similar one carried out here in Australia.

"There are a few statistical geneticists who have a bit of egg on their faces for saying it wasn't going to work," he says. "It clearly does and it points the way forward.

"I think there is only one study being funded by an Australian source now to do a genome-wide association study and we basically have no mechanism for funding this, which is absurd.

"There are lots of very good population cohorts in Australia which would be very informative but there needs to be a mechanism to come up with funding, because this approach is going to be applied across all major diseases. We are going to see that most genes for most common diseases will be identified through this approach."

Brown says one of the criticisms of the study was that not many genes were identified and, individually, they had a weak effect.

"But for type 1 diabetes they have identified more than half of the genetics just through this one study," he says. "Just because a gene is said to be worth only a proportion of the risk of the disease, that doesn't mean it is not important to everyone with the disease.

"You've identified that genetic variation is responsible for a proportion, but this study says it is a really critical part of that disease. That's important."

Rheumatoid arthritis

Brown's principal area of research is ankylosing spondylitis (AK), a chronic inflammatory disease of the spine and sacroiliac joints. He has been researching human rheumatic diseases at Oxford University since 1994, returning to Australia in 2005 to take up the position at the Diamantina Institute, where he is also program head of the immunology research program.

The rheumatoid arthritis studies in the consortium were led by Jane Worthington and her team from the University of Manchester. Their results confirmed what was already known about the genetic underpinnings of the disease in Caucasians: an association between rheumatoid and alleles of the HLA-DRB1 gene, as well as an association with PTPN22. Brown says both of those were strongly significant in the Wellcome Trust study.

"But there were other genes that came up too, including a link with the IL2 receptor," Brown says. This receptor is thought to have an important role in preventing autoimmunity. Brown says IL2RA is one of the 58 'very likely' genes, partly because one of the other very likelies is IL2RB.

"IL2RA seems to be linked with type 1 diabetes, as does PTPN22, which we knew. We also already knew that there was a clinical link between type 1 diabetes and rheumatoid, so that wasn't surprising.

"What was a bit surprising was the link across IL2RA and Crohn's disease. That suggests there is some shared immunopathology between those three conditions.

"That finding with IL2 is something that could be easily targeted therapeutically, so it's one of the findings that could very quickly lead to new trials."

While the AS data has not yet been published, Brown is able to confirm that a major gene for AS has been identified: the interleukin-23 receptor (IL-23R), which has also been linked to Crohn's disease.

"This is worth about 12 per cent of the inheritance of AS, which means it has a very large genetic effect and it is another one that will very likely lead to human treatments in the near future."

Population structure

One of the most fascinating things to come out of the study was the evidence of natural selection at work within the population. The 14,000 cases studied were all of British background and self-identified themselves as white European, as did the 3000 controls, half of whom came from the 1958 British Birth Cohort and half from donors to the UK blood service. (Some samples had to be excluded when evidence of non-Caucasian ancestry arose.)

The study found that the British population is heterogeneous, having been shaped by several waves of immigration from southern and northern Europe. The data identified 13 different genomic regions showing strong geographical variation.

"The predominant pattern is variation along a NW/SE axis," the authors write. "The most likely cause for these marked geographical differences is natural selection, most plausibly in populations ancestral to those now in the UK."

As others have identified previously, the study found variation due to selection in LCT (lactase) and MHC (major histocompatibility complex), but others have now come up.

"The finding that there were only a very small number of restricted regions where there was much genetic variation across the UK, and that that was pretty much all ascribable to two genes that were related to basic immunity and nutritional effect," is quite extraordinary, Brown says.

"It is also extraordinary that we would be seeing in a population that was born in 1958 effects that were due to the presence of plague, TB, pellagra and a dependence on dairy products for nutrition - it's just amazing."

More study results will be released in the next few months.