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Just before his appointment as head of the US National Institutes of Health (NIH), Francis Collins, the most prominent medical geneticist of our time, had his own genome scanned for disease susceptibility genes. He had decided, so he said, that the technology of personalised genomics was finally mature enough to yield meaningful results. Indeed, the outcome of his scan inspired The Language of Life, his recent book which urges every individual to do the same and secure their place on the personalised genomics bandwagon.
So, what knowledge did Collins's scan produce? His results can be summarised very briefly. For North American males the probability of developing type 2 diabetes is 23%. Collins's own risk was estimated at 29% and he highlighted this as the outstanding finding. For all other common diseases, however, including stroke, cancer, heart disease, and dementia, Collins's likelihood of contracting them was average.
Predicting disease probability to within a percentage point might seem like a major scientific achievement. From the perspective of a professional geneticist, however, there is an obvious problem with these results. The hoped-for outcome is to detect genes that cause personal risk to deviate from the average. Otherwise, a genetic scan or even a whole genome sequence is showing nothing that wasn't already known. The real story, therefore, of Collins's personal genome scan is not its success, but rather its failure to reveal meaningful information about his long-term medical prospects. Moreover, Collins's genome is unlikely to be an aberration. Contrary to expectations, the latest genetic research indicates that almost everyone's genome will be similarly unrevealing.
We must assume that, as a geneticist as well as head of NIH, Francis Collins is more aware of this than anyone, but if so, he wrote The Language of Life not out of raw enthusiasm but because the genetics revolution (and not just personalised genomics) is in big trouble. He knows it is going to need all the boosters it can get.
What has changed scientifically in the last three years is the accumulating inability of a new whole-genome scanning technique (called Genome-Wide Association studies; GWAs) to find important genes for disease in human populations1. In study after study, applying GWAs to every common (non-infectious) physical disease and mental disorder, the results have been remarkably consistent: only genes with very minor effects have been uncovered (summarised in Manolio et al 2009; Dermitzakis and Clark 2009). In other words, the genetic variation confidently expected by medical geneticists to explain common diseases, cannot be found.
There are, nevertheless, certain exceptions to this blanket statement. One group are the single gene, mostly rare, genetic disorders whose discovery predated GWA studies2. These include cystic fibrosis, sickle cell anaemia and Huntington's disease. A second class of exceptions are a handful of genetic contributors to common diseases and whose discovery also predated GWAs. They are few enough to list individually: a fairly common single gene variant for Alzheimer's disease, and the two breast cancer genes BRCA 1 and 2 (Miki et al. 1994; Reiman et al. 1996). Lastly, GWA studies themselves have identified five genes each with a significant role in the common degenerative eye disease called age-related macular degeneration (AMD). With these exceptions duly noted, however, we can reiterate that according to the best available data, genetic predispositions (i.e. causes) have a negligible role in heart disease, cancer3, stroke, autoimmune diseases, obesity, autism, Parkinson's disease, depression, schizophrenia and many other common mental and physical illnesses that are the major killers in Western countries4.
For anyone who has read about 'genes for' nearly every disease and the deluge of medical advances predicted to follow these discoveries, the negative results of the GWA studies will likely come as a surprise. They may even appear to contradict everything we know about the role of genes in disease. This disbelief is in fact the prevailing view of medical geneticists. They do not dispute the GWA results themselves but are now assuming that genes predisposing to common diseases must somehow have been missed by the GWA methodology. There is a big problem, however, in that geneticists have been unable to agree on where this 'dark matter of DNA' might be hiding.
If, instead of invoking missing genes, we take the GWA studies at face value, then apart from the exceptions noted above, genetic predispositions as significant factors in the prevalence of common diseases are refuted. If true, this would be a discovery of truly enormous significance. Medical progress will have to do without genetics providing "a complete transformation in therapeutic medicine" (Francis Collins, White House Press Release, June 26, 2000). Secondly, as Francis Collins found, genetic testing will never predict an individual's personal risk of common diseases. And of course, if the enormous death toll from common Western diseases cannot be attributed to genetic predispositions it must predominantly originate in our wider environment. In other words, diet, lifestyle and chemical exposures, to name a few of the possibilities.
The question, therefore, of whether medical geneticists are acting reasonably in proposing some hitherto unexpected genetic hiding place, or are simply grasping at straws, is a hugely significant one. And there is more than one problem with the medical geneticists' position. Firstly, as lack of agreement implies, they have been unable to hypothesise a genetic hiding place that is both plausible and large enough to conceal the necessary human genetic variation for disease. Furthermore, for most common diseases there exists plentiful evidence that environment, and not genes, can satisfactorily explain their existence. Finally, the oddity of denying the significance of results they have spent many billions of dollars generating can be explained by realising that a shortage of genes for disease means an impending oversupply of medical geneticists.
You will not, however, gather this from the popular or even scientific media, or even the science journals themselves. No-one so far has been prepared to point out the weaknesses in the medical geneticist's position. The closest up to now is from science journalist Nicholas Wade in the New York Times who has suggested that genetic researchers have "gone back to square one." Even this is a massive understatement, however. Human genetic research is not merely at an impasse, it would seem to have excluded inherited DNA, its central subject, as a major explanation of most diseases.
The failure to find major 'disease genes'
Advances in medical genetics have historically centered on the search for genetic variants conferring susceptibility to rare diseases. Such genes are most easily detected when their effects are very strong (in genetics this is called highly penetrant), or a gene variant is present in unusually inbred human populations such as Icelanders or Ashkenazi Jews. This strategy, based on traditional genetics, has uncovered genes for cystic fibrosis, Huntington's disease, the breast cancer susceptibility genes BRCA 1 and 2, and many others. Important though these discoveries have been, these defective genetic variants are relatively rare, meaning they do not account for disease in most people2. To find the genes expected to perform analogous roles in more common diseases, different genetic tools were needed, ones that were more statistical in nature.
The technique of genome wide association (GWA) was not merely the latest hot thing in genetics. It was in many ways the logical extension of the human genome sequencing project. The original project sequenced just one genome but, genetically speaking, we are all different. These differences are, for many geneticists, the real interest of human DNA. Many thousands of minor genetic differences between individuals have now been catalogued and medical geneticists wanted to use this seemingly random variation to tag disease genes. Using these minor DNA differences to screen large human populations, GWA studies were going to identify the precise location of the gene variants associated with susceptibility to common disorders and diseases.
To date, more than 700 separate GWA studies have been completed, covering about 80 different diseases. Every common disease, including dozens of cancers, heart disease, stroke, diabetes, mental illnesses, autism, and others, has had one or more GWA study associated with it (Hindorff et al. 2009). At a combined cost of billions of dollars, it was expected at last to reveal the genes behind human illness. And, once identified, these gene variants would become the launchpad for the personalised genomic revolution.
But it didn't work out that way. Only for one disease, AMD, have geneticists found any of the major-effect genes they expected and, of the remaining diseases, only for type 2 diabetes does the genetic contribution of the genes with minor effects come anywhere close to being of any public health significance (Dermitzakis and Clark 2009; Manolio et al. 2009). In the case of AMD, the five genes determine approximately half the predicted genetic risk (Maller et al. 2006). Apart from these, GWA studies have found little genetic variation for disease. The few conclusive examples in which genes have a significant predisposing influence on a common disease remain the gene variant associated with Alzheimer's disease and the breast cancer genes BRCA1 and 2, all of which were discovered well before the GWA era (Miki et al. 1994 and Reiman et al. 1996).
Though they have not found what their designers hoped they would, the results of the GWA studies of common diseases do support two distinct conclusions, both with far-reaching implications. First, apart from the exceptions noted, the genetic contribution to major diseases is small, accounting at most for around 5 or 10% of all disease cases (Manolio et al. 2009). Secondly, and equally important, this genetic contribution is distributed among large numbers of genes, each with only a minute effect (Hindorff et al. 2009). For example, the human population contains at least 40 distinct genes associated with type I diabetes (Barrett et al. 2009). Prostate cancer is associated with 27 genes (Ioannidis et al. 2010); and Crohn's disease with 32 (Barrett et al. 2008).
The implications for understanding how each person's health is affected by their genetic inheritance are remarkable. For each disease, even if a person was born with every known 'bad' (or 'good') genetic variant, which is statistically highly unlikely, their probability of contracting the disease would still only be minimally altered from the average.
DNA is not the language of life or death
This dearth of disease-causing genes is without question a scientific discovery of tremendous significance. It is comparable in stature to the discovery of vaccination, of antibiotics, or of the nature of infectious diseases, because it tells us that most disease, most of the time, is essentially environmental in origin.
But such significance leaves a puzzle. Huge quantities of newspaper space has been devoted to genes, or even to hints of genes for various diseases5. By rights then, reports of the GWA results should have filled the front pages of every world newspaper for a week. So, why has this coverage not occurred?
It is possible to conceive of excuses for lack of coverage: refutation is inherently less interesting, and the GWA results have been reported piecemeal, but the more likely reason is the disturbing implications for medical geneticists who are its discoverers. The GWA studies were not envisaged as a test of the hypothesis: do genes cause common diseases? Rather, they were expected merely to straightaway identify the guilty genes that everyone "knew" were there. By apparently refuting the entire concept of genes for common diseases, the GWA studies raise fundamental questions about money spent, hopes raised, and judgments made by medical researchers.
In the first place, the GWA results raise what are probably insurmountable questions for the prospective 'genetic revolution' in healthcare. What use will personalised DNA testing (or sequencing) be if genes cannot predict disease for the vast majority of people? Are genes with only extremely minor effects going to be of value as drug targets? How hard is it going to be to untangle their roles in disease when they have hardly any measurable effect? Should we still suppose that pouring more resources into human genetic research is going to rescue industry's faltering drug development pipelines? All of a sudden, the future of medicine, especially in the specialities dealing with degenerative diseases and mental illness, looks very different and a lot less promising. We no longer have a 'complete transformation' to look forward to, only a continuation of the incremental improvements and setbacks that have characterised medicine for the last fifty years.
Shoring up the good ship medical genetics
In a rare public sign of the struggle to come to terms with this genetically impoverished world-view, the authors of a brief review in Science magazine, Andrew Clark of Cornell University and Emmanouil Dermitzakis of the University of Geneva Medical School, Switzerland have been alone in stating the case even partly straightforwardly. According to them, the GWA studies tell us that "the magnitude of genetic effects is uniformly very small" and therefore "common variants provide little help in predicting risk" (Dermitzakis and Clark 2009). Consequently, the likelihood that personalised genomics will ever predict the occurrence of common diseases is "bleak". This aim, they believe, will have to be abandoned altogether.
The first conclusion to be drawn from these quotes is that such directness implies that if the GWA findings are not finding their way to the front page the reason is not ambiguity in the results themselves. From a scientific perspective the GWA results, though negative, are robust and clear.
Most human geneticists view the GWA results somewhat differently, however. An invited workshop, convened by Collins and others, discussed the then-accumulating results in February 2009. The most visible outcome of this workshop was a lengthy review published in Nature and titled: "Finding the Missing Heritability of Complex Diseases." (Manolio et al. 2009).
For a review paper that does not lay out any new concepts or directions, 27 senior scientists as coauthors might be considered overkill. "Finding the Missing Heritability", however, should be understood not so much as a scientific contribution but as an effort to conceal the gaping hole in the science of medical genetics.
In their Science article, which was published almost simultaneously, Dermitzakis and Clark paused only briefly to consider whether so many genes could have been overlooked. Apparently, they thought it an unlikely possibility. Manolio et al., however, frame this as the central issue. According to them, since heritability measurements suggest that genes for disease must exist, they must be hiding under some as-yet-unturned genetic rock. They list several possible hiding places: there may be very many genes with exceedingly small effects; genes for disease may be highly represented by rare variants with large effects; disease genes may have complex genetic architectures; or they may exist as gene Copy Number Variants (CNVs). Since Manolio et al. presented their list, the scientific literature has seen further suggestions for where disease genes might be hiding. These include in mitochondrial DNA, epigenetics and in statistical anomalies (e.g. Eichler et al. 2010; Petronis 2010).
A problem for all these hypotheses, however, is that anyone wishing to take them seriously needs to consider one important question. How likely is it that a quantity of genetic variation that could only be called enormous (i.e. more than 90-95% of that for 80 human diseases) is all hiding in what until now had been considered genetically unlikely places? In other words, they all require the science of genetics to be turned on its head. For epigenetics, for example, there is scant evidence that important traits can be inherited through acquired modifications of DNA. Similarly, if rare variants with strong effects keep appearing in the population and causing major illnesses, why is there no evidence for this phenomenon, since it must have been occurring in the past? With unanswered questions such as these, it is unsurprising that none of the mooted explanations has attracted any kind of consensus among geneticists and in fact the CNV explanation is already looking highly unlikely (Conrad et al. 2010; The Wellcome Trust Case Control Consortium 2010). As the first of these two papers summarised "we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by CNVs" (Conrad et al. 2010).
Now, it is not impossible that human diseases follow unique genetic rules, but the apparently overlooked possibility is that the GWA studies are indicating a simple truth: that genes are not important causes of major diseases.
As stated so far, the case against the importance of genes for disease seems strong. However, the 'missing heritability' argument is based on numerous predictions of a large genetic contribution to human diseases that are derived from heritability measurements. These heritability estimates are obtained from the study of identical and non-identical twins. A crucial question becomes, therefore, are these estimates truly reliable?
How robust is the historical evidence for genetic causation?
A perennial feature of research into human health has always been the mountain of evidence that environment is overwhelmingly important in disease. People who migrate acquire the spectrum of diseases of their adopted country. Populations who take up Western habits, or move to cities with Western lifestyles, acquire Western diseases, and so on (e.g. Campbell and Campbell 2008). These data are hard to refute, not least because they are so simple, but geneticists, when discussing them, invariably wheel out their own version of incontrovertible evidence: twin studies of the heritability of complex diseases. When Francis Collins talks about 'missing heritability' it is to studies such as these that he is referring. They provide the basic evidence for genetic influences on human disease.
A classic example of this contradiction is myopia. A large body of evidence suggests that myopia is an environment-induced disorder caused by some combination of night lighting, close reading, lack of distance viewing and diet (e.g. Quinn et al. 1999). Moreover, under the influence of Westernisation, genetically unchanged populations, for example, are known to have switched in a single generation from close to 0% to a prevalence of myopia of over 80% (Morgan 2003). And myopia is only one of many examples of diseases with very strong evidence for its environmental origin. In 2009, for example, researchers demonstrated that very moderate improvements in lifestyle could reduce an individual's probability of contracting type 2 diabetes by 89% (Mozzafarian et al. 2009). The subjects of this study just had to smoke less than the average, keep trim, exercise moderately and not eat too much fat.