Monday, May 4, 2009

How complex is 'complex'?

The word 'complex' is frequently used, though not always as clearly as it might be. In today's genetics arena it means a trait that is the result of multiple genetic elements as well as environmental factors that are usually unknown or not specified, but can include the genetic element's genomic background. Can we get a clearer understanding of this interaction in some way that has not yet been well-explored?

Most complex traits, whose genetic contributors GWAS and related mapping methods are designed to find (see earlier posts) show substantial evidence of being 'genetic' in some sense: there is correlation of the trait among relatives or an association of risk of the trait--like a disease--among family members.

The problem is that despite evidence for genetic involvement, GWAS and other methods have only been able to identify a small fraction of the contributing elements. One response is that we need larger studies. Another is that the objective is not to account for the disease in terms of genes, but to find genetic pathways that are involved.

Most common diseases have increased substantially, if not dramatically, within living memory and more importantly within the time since trustworthy epidemiological data on incidence (rate of new cases per year) or prevalence (fraction of persons affected) have been available.

This would suggest to reasonable people, even including some geneticists, that at least for preventive purposes the major responsible (and avoidable) factors for the disease are environmental, such as exposures to risk factors like toxins, lifestyle changes such as in diet, etc.

A few years ago, the molecular technology infrastructure for mapping studies was laid down, and paid for on the rationale that common genetic variants were likely responsible for these common diseases--and hence that genetics was a right way to approach them. Common variants for common disease (CVCD) became a mantra.

In response to the environmental and other arguments raised even at the time, proponents of CVCD and the investment in the gene-mapping infrastructure (e.g., the HapMap project) said that, yes, environmental factors clearly were involved, but the increase in prevalence was due to their interaction with common genetic susceptibility variants.

Subsequent mapping, including numerous, often huge genomewide association studies, has generally failed to find such variants. The meaning of 'common' can of course be adjusted to fit results, but the bulk of the heritability of these many studied traits remains unexplained. It's a fair question whether these traits are truly complex and largely unmappable, or whether we just haven't studied them enough.

A kind of widespread relevant evidence may be the following. The substantial heritability of common disease as well as normal traits suggests that many genes contribute; the traits are often called 'polygenic' for that reason. But these many genes might individually vary in their effects. For many theoretical and empirical reasons, one would expect some alleles (genetic variants) at one or a few genes, to interact or respond more strongly to changing environmental factors.

If that is the case, then the more important genes that were not identifiable in case-control or family samples before the environmental change, should be mappable afterward. That's because those variants that would be the main responders to the environmental change, whatever it was. Their individual effects, modest before the change, should be major after it.

Yet, today, after a long list of diseases have had large, rapid increases in prevalence, the GWAS findings are as we have seen: they are not identifying much that is of population-scale importance. On the surface, this suggests that the argument about complexity really is correct: there are, indeed, many genes involved, but they each make very small net effect on risk. A few are detected whose effects are greater, but they are few and even their effects are only modest.

From this perspective, which is based on data, not theory, secular trends in risk and the failure of GWAS to find CVCD's is relevant data, suggest that complex traits really are basically homogeneous in terms of genetic causation.

Now, if this is true it constitutes material evidence that should change our understanding of the nature of these traits: why would it be that there are generally no major alleles waiting for environmental changes to give them a chance to be expressed? Indeed, isn't that just how natural selection is supposed to work, with environmental change favoring 'good' genetic variants in the population and raising them to high frequency? Those variants should have substantial effect on the trait so the organism carrying the variants would reproduce more successfully.

If our thinking is correct, then this tells us something. Perhaps the networks of which biological traits are built are internally adjusting--strong changes in one part of a pathway network lead to slowing down of others. Yet, secular trends show that the net result can involve major change. It is indeed somewhat difficult to believe that the genetic responses to environmental changes are so internally homogeneous that even after major stimulus none really stands out even when studied in large samples. There must be a message there--if we can but figure it out!

These are just superficial ideas at this point, but they could help direct changes in what we look for, or how we look. We are starting to use an evolutionary simulation program that Brian Lambert in our group has written (see the description of ForSim on Ken's web page for details) to see if this point is correct as we think, or if there is some aspect of genetic control that we are overlooking. Stay tuned for results.

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