Monday, June 15, 2009

The simple facts of life

Here we report on some reflections after our participation in a meeting on the 'New Genomics in Medicine and Public Health' held at the University of Bristol, UK. The talks were varied and interesting, including a talk about Mendel, reports of successful and unsuccessful genomewide association studies, plaudits for the UK Biobank, and discussion of clinical applications of genomic findings.

An important question these days, related to various methods in genetics and its role in medicine and public health, is how causally complex life really is--a question at the heart of most of the work reported at the meeting. Some normal traits as well as diseases clearly are genetic, in that their variation is clearly caused by variation in a single gene (or a small number of genes, in a way that's well understood). But others are less clear cut, as we've discussed here a number of times.

Vested interests of all sorts, including venal and careerist interests, but also strongly held scientific conviction affect this area these days. One way to put the question is: "How causally complex is life?" Here the interest is mainly in genes, environment getting some but usually rather casual or minimal attention, and the question boils down to how well phenotypes can be predicted from known or knowable genotypes. Sometimes this means using individual variation to predict individual disease risk--this is the major original purpose of GWAS (genome-wide association studies). Sometimes it means using natural variation as a tactic to identify genetic pathways that are responsible for some normal trait; the idea here is either that, when mutant, the pathway (or 'systems' or 'network') genes could lead to disease and/or that these genes, when known, can be used as general preventive or therapeutic targets.

A commonly invoked motivation for human genetics work these days is that we will be able to implement 'personalized medicine', to predict disease or treatment, or to suggest preventive measures, based on each person's genotype. Many companies are promoting this, and the molecular genetics community is hyping it very heavily (here, there is no doubt of strong material vested interests, even if some actually believe it will work as advertized).

There are hundreds of diseases for which a, or often the causative gene is known. Sickle cell anemia, Huntington disease, Phenylketonuria (PKU), Cystic fibrosis (CF), and Muscular dystrophy (MD) are just a few examples. For these, predictive power already exists, though clinical application is not necessarily based on genotype. There are other examples where the latter is true, but these are generally rare in the population. Promising gene-based molecular therapy is in the works for CF, MD, and maybe even for some forms of inherited breast cancer (due to BRCA1/2 mutations). For these diseases, causation is clear even if there are substantial variation in risk, age of onset, or severity. Causation here is usually thought of as simple.

But for most common and/or chronic diseases, the story is far from clear as we've mentioned in various earlier posts (and as is widely discussed in the literature). These traits usually have substantial heritability (i.e., familial risk--if a close family member is affected, your chance of getting the same disease is greater than that of a random member of the population to which you belong). That means that, unless we are somehow badly understanding things, genetic variation plays a major role in risk (at least in current environments). Yet after many sophisticated, large studies, identified genes account for only a small fraction of the familial risk. The data suggest that many genes, say 'countless' genes, contribute substantial risk in aggregate, but individually their contribution is so small as to be unidentifiable by feasible (or cost-justifiable) studies. That would suggest that the disorder is caused by numerous combinations of huge numbers of individually weak, and rare, genetic variants. This is known classically as 'polygenic' inheritance, and if it's what's going on, things are very complex indeed.

Others, focused on the many clearly 'Mendelian' (single-gene) traits, simply don't believe life is that complicated. They suggest at least two other possibilities. One is that only a modest number of genes contribute, but most of the culpable alleles (sequence variants) are so rare and weak that genomewide association studies cannot pick them up. At such genes, there may be one or two strong, common alleles and these have high penetrance (when present, the disease usually occurs) and so they can be identified in family or GWAS. Those variants only account for a small amount of overall genetic contributions. But once the gene is known, we can sequence it in many patients and, lo and behold!, we find many other alleles that, some argue, contribute the rest of the observed family risk.

There is some truth to this: we have done simulations to show that there can be high heritability but only a few contributing genes, for just such reason (heterogeneity of the frequency and effects of existing alleles).

Another possibility is that a modest number of genes have variants with rare, but not very rare frequency. These will be identified by the panoply of existing methods, and once that's done it will be possible to genotype everyone at these genes, identify each person's individual set of variants, and determine risk. These are called 'oligogenic' effects, because the number of genes involved is small rather than huge. This view acknowledges the current problem, but assumes it will go away with enough data--and, importantly, that business as usual is a right approach.

Presentations at the Bristol meeting, including Ken's, show clearly that causation is a spectrum of aggregate vary rare genetic effects, a larger but still small fraction of oligogenic effects, major gene effects, and polygenic effects.

The question is: what do we do if this is true? Where is the practical limit below which attempts to identify all the genes are futile or not worth the investment, and is it likely that current attempts will at least identify the bulk of genetic effects and the networks involved so that the disease can be eliminated in whole or at least major part?

There is no single consensus in this area. Some are more skeptical than others. Some argue that knowing the genetic contributions to disease may make diagnosis more specific (the doctor can test for which gene is contributing to a given case), even if genotype-based prediction will remain a dream in the eyes of venture capitalists. Other computophiles believe that if enough computers are used on enough DNA sequence, the problem will, like infectious diseases, be solved. We won't be sick any more.

Time will tell where in the causal spectrum most traits lie. One thing we can be sure of, though: in this contentious area in which huge career, institutional, and commercial investments are at stake, in years to come, retrospective evaluation will always claim victory! Few will look back and say that we knew better than to make the level of investment in genetic causation that we are currently making.

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