Thursday, August 6, 2009

GWAS: Carry on regardless....(?)

From 1958-78,29 very funny British 'Carry on' movies, with titles like 'Carry on nurse,' were produced. It's a British phrase that a boss would say to an employee, but in this case, no matter how bollixed up the situation was, the idea was that people just 'carry on' regardless. The movies parodied British institutions and their behavior.

Well, though it's neither satirical nor funny, the same is often the case in science, where the thing-to-do is what's done regardless of whether it's the best thing or is working very well. We cling to our flotsam if it's all we know or seems the safest.

On July 14, we wrote about a Nature paper describing the results of a genome-wide association study (GWAS) of the genetics of schizophrenia, published online. This and two accompanying papers appear in the journal this week, reinforcing the story of schizophrenia as a polygenic trait, with many genes involved, each with very small effect. The papers suggest that the immune system may somehow be involved, as genes in the HLA system are found to have a significant, if limited effect, as well as some aspects of brain development, cognition and memory.

This is potentially very interesting because if GWAS are finding anything it may be that immune or inflammatory system genes are involved in a wide array of traits, perhaps not always previously suspected as such. Could infectious or autoimmune causes be more widespread than we have suspected? If so, it may say a lot. Partly it could be the things that go wrong over a life that's decades long, in terms of exposures and/or mutations that attack self.

But this and a host of other GWA studies have had minimal findings--hyped to death, perhaps, but usually accounting for only a minor fraction of all causation, even the known genetic component as revealed by the family cluster of disease. Each study finds one or a few genes that contribute detectable amounts to the trait. Some of these have been replicated and begin to be believable for that reason (though many if not most have no a priori plausibility as causes of the mapped disease).

This should be providing geneticists with plenty of targets for real genetics, real in the sense of figuring out what the genes do and how to attack them therapeutically. Modest they may be, but they're the strongest candidates we have.

So why, then are new GWAS still being done all over the place on the same diseases? Even strong proponents of this method have acknowledged that they are finding many genes with small effect. The same traits are being studied over and over again, often finding different genes, but which almost invariably explain very little risk.

It's time to stop paying for ever more of this, and to demand proof of principle. The principle is that (1) we can show how, why, and when these candidates (and their many mutations and regulatory sequence variants) are involved in disease, and then (2) that we can do something about them. Yet, because many investigators are set up for mapping, which is after all a rather mechanical button-pushing kind of enterprise (and very grant-able), one often hears investigators saying that 'mapping is what I do' .

That's a very poor excuse, even if in a careerist society that depends on the grant system and on intellectual inertia. What we need now is some accountability: to show that the fruits of GWAS labor to date are worth it and do, after all, have important biomedical use.

That being done, we'll know better whether we should continue down the reductionist mapping road, or whether better, more effective approaches to causation, even genetic causation, are the proper course.

In the 'Carry on' movies, things muddled along despite all the confusion, and in science we'll muddle along, too. Nobody can say that persistence with GWAS or other tactics is useless, even if it's inefficient and we know better what would be better. But biomedical science can do better, and we think that it should.


spritrig said...

Yea. So what if the first researchers couldn't solve the puzzle? The data isn't being wasted. NIH dbGAP has given the schizophrenia data to 36 other primary investigators as of today (November 19, 2009).

Ken Weiss said...

We concluded this very post by saying this is not useless. There is a lot of selfishness in human genetics, but there is also a remarkable amount of cooperation, and open data bases is one good example. Francis Collins gets a lot of credit for that, as he supported public data while Genome Institute Director. And NIH generally, whoever was responsible (I don't remember) for their public accessibilities policy.

Hard problems can't be solved overnight, but it is fair to criticize persistence in things that there are reasons to think aren't going very much of anywhere, once we know that.

But that's my view, and you're of course welcome to yours!

spritrig said...

My opinion is biased. I have received access to this data and other data. If discoveries were made on the first pass, that would be less opportunity for me.

I am inspired by the existence of this data and the failures to discover! Failure to discover provides fantastic opportunities for others.

I am grateful to the people who work to create opportunities for others and to allow others to stand on their shoulders. I thank them! They deserve the thanks of every investigator who receives this data.

There is no law in science that the people who collect data make the discovery. Einstein explained the most famous failed Michelson-Moreley experiment of 1887. He also explained the photo-electric effect from Heinrich Hertz's experiments of 1887 and got the 1921 Nobel Prize.–Morley_experiment
Francis and Crick used Rosalind Franklin's data.
Data sharing means more researchers get data access legitimately, and the rights of participants are defined if not legally secured. This is a great advance.

I believe the Wellcome Trust is responsible for data sharing.

spritrig said...

It is the job of the funders to allocate resources where they provide maximum benefit.

I admit it was very refreshing to read in this blog and others that the hoopla surrounding announcements of GWAS results is recognized. It should be talked about.

Ken Weiss said...

I think funders allocate resources for much more complicated reasons than 'where they will provide maximum benefit', though that is often the rhetoric, and maybe even the funders' intent. But it involves many more, and deeper aspects of our culture how resources, even in science, are allocated.

The latest schizophrenia paper we've seen was in Science and estimated that many thousands of genes contribute. So if you solve the problem especially from GWAS data, you'll certainly deserve an awared, and it will show how good the data sharing that does take place is.

spritrig said...

I have gotten enough irrational rejections that I have to agree with 'maximum benefit' being rhetoric. I have found the Wellcome Trust to be very strait forward.

I'm taking a little vacation from GWAS analysis. Getting this data set was unexpected but very appreciated. I am recovering from issues in another GWAS data set.

I really appreciate the number of bloggers are pointing out important issues. Thanks!

spritrig said...

The coverage of coding SNPs on microarrays is very poor.