I wrote a few days ago about a debate in the New England Journal of Medicine over the value of data emerging from recent genome-wide studies of the role of genetic variation in common human diseases and other traits. David Goldstein argued that genome-wide association studies (GWAS) have generated disappointing results, and should be scaled back in favour of whole-genome sequencing; Joel Hirschhorn responded with an upbeat piece emphasising the insights generated by GWAS into the molecular basis of common diseases.
Now geneticist Steve Jones has an opinion piece in the Telegraph that translates Goldstein’s argument into lay terms, although without ever actually citing Goldstein – instead, he describes “a pack of renegade biologists [that] has turned on [the Wellcome Trust, the body funding many GWAS] to claim that what it is doing is welcome, but plain wrong”. He also repeats Goldstein’s argument that whole-genome sequencing should replace GWAS as the major focus of geneticists:
…many geneticists now think that the constant pressure to
sample thousands and thousands more people for a myriad of unknown
genes that have a tiny effect may be misplaced. Instead, we would be
better off abandoning the scattergun approach, and reading off the
entire three thousand million DNA letters of a much smaller number of
individuals, healthy and unhealthy, to see in detail what might have
The Telegraph then uses Jones’ article as the template for a truly awful piece of science journalism that gives the impression that all of the money spent on genetic research over the last few years has been wasted, and that Jones has been forced to step in to put things right:
Prof Jones, who does not name the other scientists, said the idea
that the research would be a “cure all” for many common illnesses such
as cancer and diabetes had led scientists down a “blind alley” and they
must now rethink their approach.
His intervention is likely to
trigger a debate into the usefulness of genetic research and on whether
the hundreds of millions invested would be better spent elsewhere.
Sure – the discussion going on in that obscure New England Journal of Medicine
rag was unlikely to spur much interest in the clinical impact of modern
genetic research; but now Prof Jones has written about it in the Telegraph researchers will really be forced to have a good hard think about these issues.
Let me make this perfectly clear: regardless of the debate over how
money should best be spent on genetic research in the future, GWAS have
not been a waste of research funding. Sure, there was some hype about the
potential predictive value of common genetic variants that has turned
out to be unjustified, but GWAS have nonetheless generated insight into the genetic basis of common disease of unprecedented scale, resolution and accuracy.
In the last few years GWAS have moved complex disease genetics from a mere handful of well-validated genetic associations to over 400 replicated signals in over 70 diseases and traits. These signals have provided insight into the genetic architecture of common diseases (something we could only guess at previously), and implicated completely unexpected molecular pathways in the basis of diseases such as macular degeneration and Crohn’s disease.
Crucially, they have also provided the impetus required for researchers to begin assembling DNA samples from massive cohorts of disease patients (often through international collaborations involving dozens of teams), which can now serve as a nucleus for more detailed genetic analysis as DNA sequencing technology improves.
Sure, the variants discovered have tended to have small effects on disease risk (as many researchers predicted based on evolutionary considerations), making them of limited value for clinical prediction; certainly there’s no question that we have a huge amount still to learn about the genetic basis of these diseases. That doesn’t negate the tremendous value of these studies to the field of human genetics. Nor, in fact, does it mean that we should now abandon them.
Large-scale DNA sequencing will undoubtedly drive the next major technological transformation in human genetics; already, there are studies around the world using second-generation sequencing platforms to survey the genetic basis of diseases (both common and rare). However, while these technologies are rapidly dropping in price it is not yet feasible to perform massive whole-genome sequencing studies involving thousands of patients – yet such large studies are precisely what is required to provide the statistical power to interpret whole-genome sequencing data.
At this stage it’s completely unclear that whole-genome sequencing on small numbers of patients – the only currently affordable project design – will provide any more insight into the genetic basis of complex disease than GWAS have. As such it makes sense to adopt a two-pronged approach: (1) take advantage of continual improvements in GWAS technology (e.g. the incorporation of lower-frequency genetic variants) to continue mining the assembled cohorts of patients and controls; and (2) develop and apply evolving large-scale sequencing technology to perform targeted studies of disease on an increasing scale. In a couple of years the two approaches will naturally meet in the middle, with cheap whole-genome sequencing applied to the same massive cohorts collected by the GWAS consortiums.
Seems like a reasonable strategy, right? Well that’s exactly what researchers are currently doing, and there’s every reason to expect that it will ultimately provide deep – and clinically relevant – insights into the genetic underpinnings of human disease. Leading GWAS researcher Peter Donnelly provides one of the few moments of clarity in the Telegraph piece: “It may be years – decades, even – before this knowledge is translated
into new treatments, but such research is essential if we are to make
So here’s my summary of this debate so far. Goldstein’s article provided a reasonable (if perhaps somewhat exaggerated) note of caution regarding the value of GWAS studies; such notes are important to ensure the field stays on track. Jones has now repeated the same caution in a more public venue, with a profoundly unnecessary extra dose of hyperbole (witness the last paragraph: the “panjandrums of science [...] with their Everest of cash” whose “mountain has laboured and brought forth not much more than a mouse”!), which does a disservice to both the funding agencies and the scientists involved.
Finally, two Telegraph reporters have whipped the debate up into an unwarranted and absurd indictment of the whole field of complex disease genetics, which will no doubt leave many readers with a sour taste in their mouth regarding the waste of their hard-earned tax dollars.
Such sourness is undeserved. While GWAS have uncovered only a fraction of the complex underpinnings of common disease genetics, the fraction they have revealed has provided unprecedented insight into the genetic architecture and molecular causes of common disease; and while debate about the future of genetic research is healthy, there is no reason why the two proposed pathways (further GWAS, and an increasing focus on sequencing) cannot co-exist.
We have a long way to go before we completely understand the basis of complex diseases such as type 2 diabetes and rheumatoid arthritis, but the field of human genetics is moving in the right direction.