Calculating your genetic risk

Monday 18 February 2013 5:30PM (view full episode)

Genome wide association studies are an efficient way of finding genes that might be important in the search for causes of common problems and new treatments for them.

The University of Oxford is a world leader in this area. Researchers there have found a surprising new gene linked to the risk of stroke. They've also uncovered some frustrating news about an important vaccine.

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The hunt for genes associated with our health and wellbeing has been on for many years now and in particular since the human genome was mapped—the genome being the DNA on our chromosomes.

But it's still too expensive and slow to go fishing for genes by sequencing—or decoding—the DNA of every single one of them. Which is why a technique called genome-wide association studies have become popular. They're a much faster way to find neighbourhoods or genes on our chromosomes which might be important in the search for causes of common problems and possibly new treatments for them.

For example, research at the University of Oxford in the UK, has found a new and surprising gene linked to the risk of stroke. They've also uncovered some frustrating news about an important vaccine.

Professor Peter Donnelly is director of the Wellcome Trust Centre for Human Genetics at the University of Oxford, which is a world leader in genome-wide association studies.

Peter Donnelly: They're large genetic studies where typically we would take—if we're focusing on a particular disease, which might be heart disease or diabetes or schizophrenia, we take a lot of people who are sick with the disease, maybe two or three or four thousand of them, and measure their genome—so their DNA—at a set of maybe half a million or a million positions. So our DNA is about 3 billion positions long, and we'd measure a selected subset of that.

We do the same in three or five or six thousand healthy people and we'd look for differences in the variance between the sick people and the healthy people. If it works well, and many of these studies have been undertaken now and they have been quite successful, what they identify are genetic variants which change people's risk of a disease, parts of the genome which matter for that disease, and then the next stage is that you actually work out what's going on biologically, and, through doing that, to get new insights into the biology of the diseases.

Norman Swan: Before we start that we're going to talk about your study of a vaccine for pneumococcus, a common cause of pneumonia and meningitis.

Peter Donnelly: That's right. It's responsible, particularly in young children, for many millions of deaths around the world each year. In developed countries vaccines have been developed which try and protect young children and have been very successful. The bacteria have a kind of capsule that protects them…

Norman Swan: A coat.

Peter Donnelly: It's a coat in effect, yes. So the vaccines which have been developed target those coats. And it's not possible to target all the possible coats. The vaccine makers have been selective. The initial vaccines targeted the coats of seven of the most dangerous types of the bacteria, and…

Norman Swan: And there have been a couple of issues about this. One is that have you knocked off those seven different types then other dangerous forms of pneumococci come in and filled the space in the ecosystem if you like.

Peter Donnelly: Yes, and indeed broadly speaking that did occur. The vaccine created a niche in the ecology of these bugs so that other types were able to expand and fill that niche. And partly because of that there's been a subsequent vaccine introduced which targets an extra six of the types of bacteria.

Norman Swan: And you've been looking at how the bug itself responded to the vaccine. That's right. They do rather clever things. It wasn't a genome-wide association study, we read most of the genome of the bug, and it turns out that the bugs do clever things. So if you think of the analogy of the vaccine as being like a policeman that's able to spot baddies who are wearing particular kinds of coats, what some of the bugs did was to swap their coats with another version of the bug which wasn't targeted by the vaccine and hence became invisible to the vaccine.

Norman Swan: The little buggars.

Peter Donnelly: Very, very cunning. Again, it had been thought that this might happen. In our study we were able to identify a number of these so-called vaccine escape changes, one of which spread quite substantially throughout the US.

Norman Swan: But it wasn't just the coat they'd swapped.

Peter Donnelly: No, that was the other interesting thing. They swapped…

Norman Swan: And scary thing…

Peter Donnelly: Yes, interesting and scary. They swapped their coats, so the vaccine didn't see them. What we saw in our study, at the same time as they swapped their coats they swapped other parts of the genome. And the thing that's scary about that is that if bacteria in this case are able to swap several distinct pieces of their genome at the same time, it allows them to kind of move through the evolutionary space quite quickly. And the worry is that if they got lucky and simultaneously swapped key parts of antibiotic resistance genes, then quite quickly antibiotic resistance, or extra-virulence, might develop.

Norman Swan: So you hope that a vaccine's going to solve your problem but it might create another.

Peter Donnelly: Standing back a bit, what we've learned are some of the mechanisms that bacteria can use to evade vaccines like this. But we've learned that that kind of thing will happen, and also we've got some understanding of the way in which new types can fill the niche. So we clearly need to be vigilant, and ideally advancing the vaccine as fast as the bugs can use evolution to escape from it.

Norman Swan: Tell me about this study on stroke.

Peter Donnelly: Yes, so we undertook a genome-wide association study of stroke. We compared the genetics of 3,500 people who had suffered from strokes with about 6,000 healthy people. Strokes arise when the blood supply to parts of the brain stops. One particular type is when there's some kind of blockage in the large arteries that feed blood to the brain.

Norman Swan: Commonly the carotid arteries in the neck get blocked and rubbish flies off and lodges in the brain.

Peter Donnelly: That's exactly right. What we found was a genetic variant that was associated with risk for that type of stroke. There's a gene unimaginably called HDAC9 and we found the variant in that gene and if you have one of the DNA letters variant at that position, your chance of this large artery stroke is increased. The variant we found is present in about 10% of the population. For people who have two copies of that—because of course we get one set of DNA from our mum and one from our dad—for people who have two copies, their risk is nearly twice that of people without the variant.

Norman Swan: So what are the implications of that finding?

Peter Donnelly: It potentially gives us a foothold into the disease. First of all our understanding of a key new mechanism in stroke, because this kind of gene wasn't suspected to be involved…

Norman Swan: Because it's not involved with blood clotting, for example.

Peter Donnelly: No, what the gene does is to mark DNA, so it's involved in the regulation of other genes. If we can understand that better there's then the possibility of being able to intervene to change whatever's happening.

Norman Swan: And tell me about this 500-person study you're doing.

Peter Donnelly: We're trying to find out which parts of what we would call genomics, so the ability to read the entire DNA sequence of people, which parts of that are closest to being ready for the clinic, for actually making a difference in routine hospital patient care. So in Oxford we're looking at 500 people chosen to have a fairly large range of different conditions. In each case trying where there's a chance that understanding the genetics better would be informative either for the diagnosis of the individual or potentially treatment or advice if there are families where children have been affected…

Norman Swan: This isn't a genome-wide association, you're just taking their whole genome and analysing it.

Peter Donnelly: Yes, it's the next step on. We're reading all 3 billion letters.

Norman Swan: And how much is it costing per genome to do this?

Peter Donnelly: It's all relative. It costs, doing a high-quality whole genome sequence probably a bit under $10,000 Australian dollars.

Norman Swan: Aiming for?

Peter Donnelly: Well, there's the much-touted goal of the thousand-dollar genome, so pries are coming down fairly rapidly.

Norman Swan: Professor Peter Donnelly.

There are already companies touting cheap gene mapping to the public and no doubt many people are tempted to look into their genetic crystal ball to avoid yet unseen landmines. But there are many issues, not the least of which are mistakes in the analysis.

Peter Donnelly again.

Peter Donnelly: It's a very serious issue in connection with studies that look at individuals' DNA. Our DNA has got 3 billion letters in it. The technologies we have for reading it aren't perfect. If you make a mistake at one in 10,000 of those positions, that's still more than 100,000 mistakes you'll have when you're looking at the DNA.

Norman Swan: But even if they were perfect and you found something, it still could be meaningless and mislead you.

Peter Donnelly: Yes. So even if they were perfect, there will be a bunch of differences that the sick people have that's special to them, and working out exactly which one of those might be the one responsible for their condition is quite tricky. So making sense of the data as we move to genomics getting closer and closer to clinical medicine is going to be a major challenge. But as you say, even if we can solve all of those problems, we will find differences in people and we don't yet have a good understanding of what the consequences of them are.

Norman Swan: How have you dealt with the ethical issue that you might find families which subsequently find it difficult to find life insurance because you've found a genetic abnormality which is in the family and they've got to declare it?

Peter Donnelly: In the UK at the moment there's a voluntary moratorium on the part of all of the insurance companies to the effect that they won't ask for and they won't use genetic information in setting insurance premiums. So that's not currently a worry. There's a potential worry at some time in the future if that position changed, but there has been that agreement in place and it's just been renewed for another I think five or six years or so.

Norman Swan: Peter Donnelly is director of the Wellcome Trust Centre for Human Genetics at the University of Oxford.


Professor Peter Donnelly
Director of the Wellcome Trust Centre for Human Genetics
University of Oxford


Dr Norman Swan
Nick Ridout

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