Tuesday, September 16, 2008

Common Disease Common Variant Dead???

I don't think so.....If that is true, I know a few comapnies out West that could have a problem.....

Turns out the publicist for my friend's friend must have gotten him a sweet article in the New York Times.

It turns out David Goldstein has been a contrarian forever. It turns out he is getting ready to publish a wonderful book. From the article

"This idea, called the common disease/common variant hypothesis, drove major developments in biology over the last five years. Washington financed the HapMap, a catalog of common genetic variation in the human population. Companies like Affymetrix and Illumina developed powerful gene chips for scanning the human genome. Medical statisticians designed the genomewide association study, a robust methodology for discovering true disease genes and sidestepping the many false positives that have plagued the field."

Well, David argues.....this idea is dead.....

“There is absolutely no question,” he said, “that for the whole hope of personalized medicine, the news has been just about as bleak as it could be.”

Wha????? David....is the common disease common variant theory equal to personalized medicine????

I would say no. What about Pharmacogenomics? I mean, come on...that's what you are studying. What about family history ascertainment? That's what you are publishing. Obviously in your mind, Personalized Medicine is not dead.

But the Common Disease Common Variant issue that is a much more interesting question.

Let's just say it is dead....as my Chairman Rick Lifton might also be in agreement with.........What happens? SNP scan testing companies go away.......Affy, Illumina, etc see a drastic cut in their machine usage and purchases (Yikes) and all the hard work we put in for the HapMap gets thrown away.....

No one is going to let that happen. So let's just say it is not dead but on the Injured reserve. If that is the case how do we rehab it.....I have some ideas

1. We need to have better methods of phenotyping and analysis. Common disease is rarely the same in everyone and is likely to have multiple etiologies

2. We need to remember that rare variants interact with common variants and look at this from a systems basis.......I.E. "Both kinds of music Country AND Western" Studies need to be designed this way

3. Lastly, we need to look at the environmental interaction with these common variants. Diet logs, career information, exposures, etc...need to be incorporated into these studies.....

Iff, we do these things and still come up with nothing, then and only then will Common Variant Hypothesis be dead!!! But with the types of ideas on the other side I don't think they get that...From Dr. Goldstein,

Just as selection turns out to have pruned away most disease-causing variants, it has also maximized human cognitive capacities because these are so critical to survival. “My best guess is that human intelligence was always a helpful thing in most places and times and we have all been under strong selection to be as bright as we can be,” he said.

This is more than just a guess, however. As part of a project on schizophrenia, Dr. Goldstein has done a genomewide association study on 2,000 volunteers of all races who were put through cognitive tests. “We have looked at the effect of common variation on cognition, and there is nothing,” Dr. Goldstein said, meaning that he can find no common genetic variants that affect intelligence. His view is that intelligence was developed early in human evolutionary history and was then standardized.

Seriously? Do you really think Hawkins type of intelligence was the same as Picasso's? What about Mozart's? Einstein's.....The statement that intelligence is standardized is crazy....There is no way a bunch of man made cognitive tests can fully stratify the phenotypes of intelligence......It sounds impressive to the lay reader. But to me....it reeks......

The Sherpa Says: While Dr Goldstein is a smart and learned individual, he will not kill of the Common Variant Hypothesis.


Anonymous said...

I think David is wrong. We need to analyse gene-gene, gene-environment interactions and epigenetics to maximize the power and applicability of the “common variant hypothesis”.

Steve Murphy MD said...

I concur,
But from a popgen standpoint....natural selection is King.....
So I understand David's slightly flawed view....B/C I have slightly flawed views all the time ;)

Joseph Terwilliger said...

David is and always has been a pro-HapMap guy. I have argued against him at meetings where he was defending the excesses of the HapMap (or as I like to call it, the CrapMap). CVCD was a stillborn baby that made no sense ten years ago when we started arguing against it, and it makes even less sense today! See my blog about this issue in http://infinnyovens.blogspot.com/ from August. CVCD died long ago, and it is nice to see one of the erstwhile sycophants for the HapMap project finally coming over to the dark side and admitting that GWAS and CVCD have been abject failures!

Joseph Terwilliger said...

As to the nonsense about analyzing gene-gene and gene-environment interactions, that makes no sense as the curse of dimensionality will completely destroy any power even assuming such interactions may characterize nature in reality. The reason studies fined "evidence" of such things is because they define the null hypothesis of "no interaction" in a mathematically contrived way that has nothing to do with actual interaction on either an etiological or biological level!

Anonymous said...

Just because gene-gene interactions and gene-environment interactions reduce statistical power does not make it irrelevant. Welcome to systems biology to help biologists and statisticians understand which gene-gene (or SNP-SNP) interactions are relevant or likely to have an effect.
I am really surprised to hear people say that the common disease common variant theory and personalized medicine is dead, or on the 'injured reserve'. Especially with the many strong findings in breast cancer (SNPs in FGFR2, Hunter 2007), mental retardation (CNV in 1q21.1, Mefford 2008), diabetes (multiple SNPs, Purcell 2007), and many other common diseases (Torkamani 2008, WTCCC 2007).
Further, with SNPs shown to have an impact on drug efficacy (CYP2D6 SNPs reducing tamoxifen efficacy is "on label" by FDA) and the predicted $1000 genome within 5 years (and some say sooner), it is unbelievable that people familiar with the field do not see the value or the inevitability of pharmacogenomics.