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The Whys of Tuberculosis

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When the idea for the Wellcome Trust Case Control Consortium was being bandied about, the University of Oxford's Adrian Hill says there was a bit of discussion about whether samples included in the project should be strictly from the UK, or from other populations as well. "In the end, the compromise was to put in Gambian populations for two diseases, as well as several diseases in the UK," Hill says. The consortium settled on malaria and tuberculosis as the Gambian portion of the project.

Today, the Wellcome Trust Case Control Consortium, or WTCCC, brings together about 50 research groups in the UK, and aims to apply genotyping methods to large population samples to get at the genetic root of a host of diseases. The consortium also provides a resource for the research community, and is now on its third stage.

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Come together

Hill's part of the Wellcome Trust Case Control Consortium is focused on figuring out what genes influence people's susceptibility to TB. To gather a TB data set, Hill's group has been working in conjunction with the Medical Research Councils Laboratory in The Gambia, a collaboration that goes back about 20 years. "TB has been one of their main targets, so they have a lot of capacity, lots of excellent, very good field work and field trial capacity, and so the collection had built up over probably 10 to 15 years by time we finished," Hill adds. Out of that collaboration, the groups identified — back in the 1990s — that variations in the N-RAMP1 gene, which plays a role in the immune system, affect TB susceptibility. As the researchers noted in their 1998 New England Journal of Medicine paper, the variant itself likely governs susceptibility and perhaps disease progression.

The analysis of the current TB data set was done in Hill's lab, in conjunction with the WTCCC's analysis group. In the Gambian data alone, however, the researchers did not find many significant hits for TB susceptibility, and had to turn to another group's data. "When we combined that with a case-control consortium from Ghana — a German group working in a Ghanaian population — we saw some rather interesting hits and a couple of those have been published and some are still being worked on," Hill says. That consortium includes researchers from the Bernhard Nocht Institute for Tropical Medicine and the University Hospital Schleswig-Holstein.

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The new genome-wide technology and methodology being used by the WTCCC changed how the Hill group worked. "Genome-wide technology put us into a different league. That's been very, very productive. Working with the Case Control Consortium was a new experience for us; we'd not been part of such a large consortium before," he says. "We learned a lot about how to work in large groupings, bring together a lot of people with statistical expertise and facing similar challenges with different diseases. Overall, it worked very well and was very productive."

Technically speaking

While Hill's TB group has faced similar challenges to what other WTCCC groups have encountered, it also had its own particular problems. Conducting a GWAS of an African population is technically challenging: African populations are more genetically diverse and have less linkage disequilibrium than non-African populations, making the interpretation of the results more complicated. Genotyping platforms generally used for GWAS in European populations did not initially provide much coverage of African populations. "LD is far less extensive in African populations than in European populations," Hill says. "In fact, some people took the view that you are just not going to find anything in Africa because nobody ever has." Now, sequencing — particularly exome sequencing — may turn the problem of genetic diversity on its head, Hill says. "Exomics in African populations is very exciting because the more extensive genetic diversity in Africans may be a real bonus for exome sequencing," he says. "It'd be more SNPs to look at and there'd be more rarer variants that might be relevant to disease susceptibility."

The findings

From the combined study of Gambians and Ghanaians, the group was able to identify a locus for TB susceptibility, as it published in Nature Genetics last year. The locus on chromosome 18 falls in a gene desert. This, Hill says, is exciting, as most previously identified disease susceptibility loci have been associated with the immune system. The team also identified another, slightly less significant locus on chromosome 2, close to the gene PARD3B. That gene, Hill notes, recently showed up in a genome-wide association study of HIV led by Stephen O'Brien at the US National Cancer Institute.

"We are working on what those genes are, on how it is relevant to disease susceptibility, and that's going to keep us going for another couple of years," Hill says. He adds that new bioinformatics tools are also allowing him and his team to re-examine their data set and examine more genes that look "very convincing."

The Breakdown

Funding: The WTCCC TB project was funded by the Wellcome Trust, though its German collaborators were funded separately.
Group Members: The Wellcome Trust Centre for Human Genetics at the University of Oxford; MRC Laboratories, The Gambia; Bernhard Nocht Institute for Tropical Medicine, Hamburg; University Hospital Schleswig-Holstein, Kiel, Germany; Kumasi Centre for Collaborative Research in Tropical Medicine, Kwame Nkrumah University, Kumasi, Ghana; Karonga Prevention Study, Chilumba, Karonga District, Malawi; and the London School of Hygiene and Tropical Medicine.

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