Thursday, April 16, 2009

GWAS: really, should anyone be surprised?

There's a story today in the New York Times about papers just published in the New England Journal of Medicine (embargoed for 6 months, so we can't link to it here) questioning the value of GWAS--genomewide association studies. We're interested because we, but largely Ken, often in collaboration with Joe Terwilliger at Columbia, have been writing for many years--in many explicit ways and for what we think are the right reasons, for 20 years or more--about why most common diseases won't have simple single gene, or even few gene explanations.

"The genetic analysis of common disease is turning out to be a lot more complex than expected," the reporter writes. Further, "...the kind of genetic variation [GWAS detect] has turned out to explain surprisingly little of the genetic links to most diseases." Of course, it depends on who's expectations you're talking about, and who you're trying to surprise. It may be a surprise for a genetics true-believer, but not for those who have been paying attention to the nature of genomic causation and how it evolved to be as it is (the critical facts and ideas have been known, basically, since the first papers in modern human genetics more than 100 years ago).

GWAS are the latest darling of the genetics community. Meant to identify common genetic factors that influence disease risk, the method scans the entire genome of people with and without the disease to look for genetic variants associated with disease risk. Many papers have been published claiming great success with this approach, and proclaiming that finally we're about to crack disease genetics and the age of personalized medicine is here. But upon scrutiny these successes turn out not to explain very much risk at all--often as little as 1%, 3% (even if the relative risk is, say 1.3--a 30% increase, or in a few cases 3.0 or more--there will always be excpetions). And this is for reasons that have been entirely predictable, based on what is known about evolution and genes.

Briefly, genes with major detrimental effects by and large are weeded out quickly by natural selection, most traits, including disease, except for the frankly single-gene diseases (which can stay around because they're partly recessive), are the result of many interacting genes, and, particularly for diseases with a late age of onset, environmental effects. And, there are many genetic pathways to any trait, so that the assumption that everyone with a given disease gets there the same way has always been wrong. Each genome is unique, with different, and perhaps rare or very rare genes contributing to disease risk and these will be difficult or impossible to find with current methods. Risk alleles can vary between populations, too--different genes are likely to contribute to diabetes in, say, Finns than in the Navajo. Or even the French. Or even different members of the same family! Inconvenient truths.

Now, news stories and even journal articles rarely point out any of these caveats. Indeed, David Goldstein is cited in the Times story as saying that the answer is individual whole genome sequencing, another very expensive and still deterministic approach (that surely will now be contorted by the proponents of big Biobanks to show that this is just the thing they've had in mind all along!). Nobody backs away from big long-term money just to satisfy what the science actually tells us. Now maybe there is the story, in the public interest, that a journalist ought to take on.

So, the push will be for ever-more complete DNA sequences to play with, but this is not in the public interest in the sense that it will not have major public health impact. Even if it identifies new pathways, one of the major rationales given in the face of the awkward epidemiological facts, which is unlikely to be a major outcome in public health terms. We have many ways to identify pathways, and more are becoming available all the time. While whole sequences can identify unique rare haplotypes or polygenotypes that some affected people share, that is really little more than trying the same method on new data, like Cinderella's wicked step-sisters forcing their feet into the glass slipper.

If it's true as it seems to be, that most instances of a disease are due to individually rare polygenotypes, then the foot will not fit be any better than before. And it won't get around the relative vs absolute risk, nor the environmental, nor the restrospective/prospective epistemiological problem. These are serious issues, but we'll have to deal with them separately. And the rarer the genotype the harder to show how often it is found in controls, hence the harder to estimate its effect.

A few reasons why no one should be surprised:

*Update* Here are a few of the papers that have made these points in various ways and contexts over the years. They have references to other authors who have recently made some of these points. The point (besides vanity) is that we are not opportunistically jumping on a new bandwagon, now that more people are (more openly) recognizing the situation. In fact, the underlying facts and reasons have been known for even a far longer time.

The basic facts and theory were laid out early in the 20th century by some of the leaders of genetics, including RA Fisher, TH Morgan, Sewall Wright, and others.

Kenneth Weiss, Genetic Variation and Human Disease, Cambridge University Press, 1993.

Joseph Terwilliger, Kenneth Weiss, Current Opinion in Biotechnology, 9(6), 578-594 (1998). Linkage disequilibrium mapping of complex disease: fantasy or reality?

Kenneth Weiss, Joseph Terwilliger, Nature Genetics 26, 151 - 157 (2000). How many diseases does it take to map a gene with SNPs?

Joseph Terwilliger, Kenneth Weiss, Annals of Medicine 35: 532-544 (2003). Confounding, ascertainment bias, and the quest for a genetic "Fountain of Youth".

Kenneth Weiss, Anne Buchanan, Genetics and the Logic of Evolution, Wiley, 2004.

Joseph Terwilliger, Tero Hiekkalinna, European Journal of Human Genetics, 14, 426–437 (2006). An utter refutation of the 'Fundamental Theorem of the HapMap'.

Anne Buchanan, Kenneth Weiss, Stephanie M Fullerton, International Journal of Epidemiology, 35(3):562-571 (2006). Dissecting complex disease: the quest for the Philosopher's Stone?

Kenneth Weiss, Genetics 179, 1741–1756 (2008). Tilting at Quixotic Trait Loci (QTL): An Evolutionary Perspective on Genetic Causation.

Anne Buchanan, Sam Sholtis, Joan Richtsmeier, Kenneth Weiss, BioEssays, What are genes for or where are traits from? What is the question? BioEssays 31:198-208 (2009).


Jennifer said...

I was just thinking along these lines this morning when on NPR they were discussing finding "the gene" for strokes. Then someone they interviewed (didn't catch who) said "genetic region". But they were still trying to put it all on genetics and having a hard time

Ken Weiss said...

Yes. And there are very good reasons, both in terms of how organisms are assembled, and how they evolved, why what we are finding is what we should expect to find....and we've had the knowledge to know that for many decades.