Wednesday, November 14, 2012

[ ] is a complex disease

The November 1 issue of Nature has a special section on autism.  Or better put, on all the things we don't know about autism, and how that has sobered researchers.  Ten years ago, or even fewer, the focus would have been on the hunt for genes for the disease, but now the recognition has set in, as this section shows, that this is a complex disorder, and genes that explain it aren't going to be found, brain scans don't yield simple answers, there is no cure, even if we knew causative genes there would be no cure, and so on.

GWAS have indeed identified hundreds of genes that are associated with autism, but they explain perhaps a percent or two of the cases.  The long-standing hope that this would be another Mendelian trait shows just how much Mendel influenced and in fact sidetracked the understanding of disease, albeit inadvertently.  The essence of a Mendelian trait, be it normal or disease, is that it is due to one (or, perhaps two or three) genes and mainly to two alleles (functionally variant states) at the gene.  This means that if one of the alleles is 'dominant' its effects are always manifest in an individual, and one has a 50% chance of inheriting the allele--and hence getting the trait--from a parent who has the allele.  Recessive traits behave similarly--one allele is responsible but only if you inherit two copies of it, one from each parent.  Again, each transmission normally occurs 50% of the time.  We're oversimplifying, but only a bit, and the gist of the message is as we describe (and we've described it before; here, e.g.).

A brief primer on 'Mendelism'
Mendelian traits segregate with these 50/50 probabilities. Sometimes the chance of having the trait even if you have the allele is less than 100%, so dominance (or what is known, mysteriously, as 'penetrance') is 'incomplete'.  When the trait really is just a single-gene trait we can understand it even with incomplete penetrance.  Even if non-genetic factors cause some instances, which are traditionally known as 'phenocopies', we can still make correct inferences, though the ability to predict a newborn's trait is compromised.
Traits that segregated in Mendel's pea plants
There are legions of well-known Mendelian diseases, of course, and we've had methods for finding genes to explain them for decades.  That has been the job of the professional clinic-associated people known as genetic counselors (because they advise parents of potential risk to their future children).  The problem is that this success is matched by the general fact that Mendelian disorders are usually quite rare in the population.  But our major health concerns today are common, not rare, and they are not Mendelian.  They aggregate in families, so that if a relative is affected your chance of being affected is raised, but they don't segregate with neatly estimable probabilities, and the reason is that they are due to the effects of many genes, each individually very small, plus complex environmental factors.

Back to autism:
So, it's complex traits like autism that we're left with now, and for these our methods are lacking.  But the problem can be described in much the same way for all complex traits.  Take this paragraph from the commentary on the genetics of autism ("Genetics: Searching for answers"), for example:
The large databases of autism gene candidates that are now available make the quest to explain autism more complicated than researchers had hoped. But the complexity of the condition is stimulating the expansion of approaches taken and enticing scientists to look beyond straightforward genetic explanations for autism. “We've figured out that explaining autism is not simple,” says Geschwind. “But I have a pretty optimistic view. We're going to continue to make progress — and a lot of it is because of great collaboration in the field and an influx of new people tackling autism.”
Substitute any complex disease for autism and it could be equally apt; heart disease, diabetes, schizophrenia, asthma, multiple sclerosis, even so-called 'simple' disorders like familial cancers or Parkinson's disease, and the same will eventually be true of rare diseases like the periodic paralyses.  The cases vary substantially, just as there's variation among people without disease (yet), and this is in part because every genome is unique and everyone is exposed to different intrauterine risk factors at different developmental stages, or during childhood and adulthood.  Science is better at explaining observations that are easily and readily replicable than it is unique events.

Wethinks the geneticist doth protest too much!
The posturing and proclamations of surprise at finding complexity is false on the part of geneticists, or else they have been very unaware of basic biological knowledge that has been around since before they were born. We had every good reason to know, decades ago (and some of us wrote as much back then) that such traits were complex--and why that was so.  The reason for the 'surprise' is that it counters the disingenuousness of the proclamations that 'the' gene(s) 'for' the trait would be found by such means as GWAS. 

The new approaches taken, looking 'beyond straightforward genetic explanations for' [whatever trait] now include all the existing omics coming online -- microbiome, connectome, metabalome, nutriome, etc -- as well as epigenomics, which is the study of alterations to DNA that are not to the gene sequence and may or may not be inherited, may or may not be due to environmental factors such as toxins, and so forth (it's interesting that this is now bringing epidemiology full circle, from environmental factors to genetics and now back to environmental factors again).  Each of these will surely explain some of the susceptibility to complex disease, but just as surely won't explain it all, or in everyone.

But hungry scientists know enough to keep coining omics categories.  So now we are seeing what,  consciously or not, amounts to using what is either feigned or culpable surprise to market even more scaled-up, larger, longer-term studies, now to include more kinds of 'omics, including very costly 'environomics' (a word we think we've just coined but that is sure to arise soon enough).

Once again, the more we know about all this, the more complex it becomes, not less. Success can eventually come from any direction of course, but we think slowing down the rat-race, calming down and spending more time thinking and less time proclaiming, more musing and less marketing, smaller and more focused rather than all-inclusive approaches would raise the odds.

And, of course, some things may just be irreducibly complicated whether we like it or not.


Marnie said...

Thanks. I've been waiting for someone to write an article like this for a while.

Ken Weiss said...

It's a hard lesson for people to accept that even the power of science can't make everything simple or simply solve every problem.

We all want answers, especially to troubling issues like disease. Many turn for solace to religion, others to science. Our tendency in science is to promise or at least hint at the prospect of easy solutions.

Hopefully, benefit will be gained by science, even if it's not simple or as soon as we'd like.

Anonymous said...

I was attending a short conference on GWAS, complex traits, and sequencing for the past few days. One of the major themes I walked away with was 'We need to sequence more samples' when talking about rare variant GWAS for complex traits. But I just don't think sequencing more people is going to be some panacea for complex disease.