Tuesday, April 21, 2009

GWAS revisited: vanishing returns at expanding costs?

We've now had a chance to read the 4 papers on genomewide association studies (GWAS) in the New England Journal of Medicine last week, and we'd like to make a few additional comments. Basically, we think the impression left by the science commentary in the New York Times that GWAS are being seriously questioned by heretofore strong adherents was misleading. Yes, the authors do suggest that all the answers are not in yet, but they are still believers in the genetic approach to common, complex disease.

David Goldstein (whose paper can be found here) makes the point that SNPs (single nucleotide polymorphisms, or genetic variants) with major disease effects have probably been found by now, and it's true that they don't explain much of the heritability (evidence of overall inherited risk) of most diseases or traits. He believes that further discoveries using GWAS will generally be of very minor effects. He concludes that GWAS have been very successful in detecting the most common variants, but now have reached the point of diminishing returns. He says that "rarer variants will explain missing heritability", and these can't be identified by GWAS, so human genetics now needs to turn to sequencing whole genomes to find these.

Joel Hirschhorn (you can find his paper here) states that the main goal of GWAS has never been disease prediction, which indeed they've only had modest success with, but rather the discovery of biologic pathways underlying polygenic disease or traits. GWAS have been very successful at this--that is, they've confirmed that drugs already in use are, as was basically also known, targeting pathways that are indeed related to the relevant disease, although he says that further discoveries are underway. Unlike Goldstein, he believes that larger GWAS will find significant rare variants associated with disease.

Peter Kraft and David Hunter (here) tout the "wave of discoveries" that have resulted from GWAS. They do say that by and large these discoveries have low discriminatory ability and predictive power, but believe that further studies of the same type (only much bigger) will find additional risk loci that will help explain polygenic disease and yield good estimates of risk. They suggest that, because of findings from GWAS, physicians will be able to predict individual risk for their patients in 2 to 3 years.

John Hardy and Andrew Singleton (here) describe the GWAS method and point out that people are surprised to learn that it's often just chromosome regions that this method finds, not specific genes, and that some of these are probably not protein-coding regions but rather have to do with regulating gene expression. Notably, unlike the other authors who all state that the "skeptics were wrong", but somehow don't bother to cite their work so that the reader could check that claim (they do cite the Terwilliger and Hiekkalinna paper we mentioned here last week, but that is on a specialized technical issue, not the basic issues related to health effects).

They also state that the idea of gene by environment interaction is a cliche, and has never been demonstrated. Whether they mean by this that there is no environmental effect on risk or simply that it's difficult to quantify (or, a technical point, that environmental effects are additive) is not clear. If the former, that's patently false--even risk of breast cancer in women who do carry the known and undoubted BRCA1 or BRCA2 risk alleles, varies significantly by decade of birth. Or the huge rise in diabetes, obesity, asthma, autism, ADHD, various cancers, and many other diseases just during the memory of at least some living scientists who care to pay attention. And, see our post of 4/18.

So, we find none of the supposed general skepticism here. Yes, these papers do acknowledge that risk explained by GWAS has been low, but they claim this as 'victory' for the method, and dismiss, minimize, or (worse) misrepresent problems that were raised long ago, and instead say either that risk will be explained with bigger studies, or GWAS weren't meant to explain risk in the first place (it's not clear that the non-skeptics agree with each other about the aim of GWAS, or about whether they have now served their purpose and it's time to move on--to methods that apparently actually do or also do explain heritability and predict risk.)

The 'skeptics' never said that GWAS would find nothing. What at least some of us said was that what would be found would be some risk factors, but that complex traits could not by and large be dissected into the set of their genetic causes in this way.

Rather than face these realities, we feel that what is being done now is to turn defeat into victory by claiming that ever-larger efforts will finally solve the problem. We think that is mythical. Unstable and hardly-estimable small, probabilistic relative risks will not lead to revolutionary 'personalized medicine', and there are other and better ways to find pathways. If a pathway (network of interacting genes) is so important, it should have at least some alleles that are common and major enough that they should already be known (or could easily be known from, say, mouse experiments); once one member is known, experimental methods exist to find its interacting gene partners.

In a way it's also a sad consequence of ethnocentric thinking to suppose that because we can't find major risk alleles in mainstream samples from industrialized populations, that such undiscovered alleles might not exist in, or even be largely confined to, smaller or more isolated populations, where they could be quite important to public health. They do and, ironically, mapping methods (a technical point: especially linkage mapping) can be a good way to find them.

But if we're in an era of diminishing, if not vanishing, returns, we're also in an era in which we think we will not only get less, but will have to spend and hence sequester much more research resources to get it. So there are societal as well as scientific issues at stake.

In any case, we already have strong, pathway-based personalized medicine! By far the major risk factor for most diabetes, for example, involves energy and fat metabolic pathways. Individuals at risk can already target those pathways in simple, direct ways: walk rather than taking the elevator, and don't over-eat!

If those pathways were addressed in this way, there would actually be major public impact, and ironically, what would remain would be a residuum of cases that really are genetic in the meaningful sense, and they would be more isolated and easier to study in appropriate genetic, genomic, and experimental ways.


Jennifer said...

so, if my fat maternal uncle and my fat paternal grandfather had diabetes, where does that leave me, genetically and environmentally? Is the risk greater for the fat part, or for the family genetics part? Would they not have gotten diabetes if they didn't get heavy? What about my children who are part black with their paternal grandmother, uncle and father having diabetes, and only the uncle being heavy?
Doesn't genetics play a part in the risk of getting that disease? And doesn't it interact with the environment, i.e. the amount and kind of food one eats and how much exercise one gets? Who's at greater risk - you or me?

Ken Weiss said...

These are all the right questions! And nobody has the answers! But here are some reactions:

1. Of course genetics plays a part, in two ways. Gene action is involved in all body functions.

2. Gene function involves response to environment, which can include all sorts of things, such as diet and activity. The word 'interaction' is used in various ways. Sometimes it means just that you are the sum of what you inherited and what you do. Sometimes it means that depending on the particular genetic variation that you carry, the same environment can have different effects. In many or most cases these two kinds of interaction are not critically to the kinds of questions you ask.

3. Anyone can get fat by too much dietary intake and storage, and not enough energy expenditure such as by activity. This is not unique to humans (ask your overfed cat!). This has little to do with genes in most cases: those who are congenitally predisposed are mostly clear-cut, and there are such cases. Adult-onset diabetes often, but not always involves overweight, for reasons that are undoubtedly partly genetic, but also probably very variable from case to case.

4. Even if your genotype affects your response to environments somewhat, each fat person is likely to have a different genotype (different variants at the many contributing genes). These can be correlated among close family members, even if they differ among families, or people from different populations. So predisposition can also be similar among family members.

5. Your family has something to do with your traits because families share behavior, diet, attitudes, and so on, as well as genes.

6. History shows, clearly I think, that if people did not overeat and had good activity levels, diabetes associated with weight (as opposed to the juvenile form of diabetes) would be much rarer. But some people would have gotten diabetes anyway: that is the subset that is truly, genetically predisposed. It does not seem to be a large number and it does seem to involve great heterogeneity in the genetic reasons for it.

7. Your children will have inherited genetic variation affecting all sorts of traits, including body shape, from both you and their father. Since only half of what you carry genetically is transmitted to any given child, and the same for their father, there is no simple prediction among relatives for this kind of trait. But most likely, if they don't get heavy, they won't get diabetes. However, these things are not simple, and not so highly predictable, generally--which is one of the problems being faced, and that we try to write about!

Ken Weiss said...

Jennifer, In my #1 part of my response I said genetics is important in two ways, but I only mentioned one of them--that genes are functional aspects of life and affect our traits.

The second way is that genetic _variation_ is associated with trait variation.

Both usually apply to varying extents.

There is actually a third way, that is not widely considered, which is that all of your cells have a slightly different genome. That's because every time a cell divides, which has been happening since you were a single cell (a fertilized egg), some mutations occur. So each person has variation they inherited in their fertilized egg, and variation that has accumulated among their cells. How important that can be depends on the circumstances, but it can be vital (as it is, for example, in cancers)

Anonymous said...

" By far the major risk factor for most diabetes, for example, involves energy and fat metabolic pathways. Individuals at risk can already target those pathways in simple, direct ways: walk rather than taking the elevator, and don't over-eat"

No. What you meant to say was "..By far the major risk factor for most TYPE II diabetes,.."

Please be accurate. Believe me, children with type I diabetes get REALLY pissed off by this lazy, inaccurate but widespread confusion. Being told that their autoimmune condition is caused by over-eating or not walking, and by implication that they brought it on themselves is a misunderstanding that would be bad enough coming from a junk TV show. But coming from someone who claims to be an expert on genetics is seriously uncool.

Anne Buchanan said...

You're right, this was lazy of us.

Ken Weiss said...

Fair enough. This was 2009, so one should check any later reports to see if the picture has changed.