Genes Show Limited Value in Predicting Diseases - Page 1

For years I have believed that OFA and other like schemes will not reduce incidence if disease very much. Here is a report of a study that I believe confirms my belief. This is just one of several that have come to the same conclusion.

April 16, 2009 NY Times
Genes Show Limited Value in Predicting Diseases

By NICHOLAS WADE
The era of personal genomic medicine may have to wait. The genetic analysis of common disease is turning out to be a lot more complex than expected.

Since the human genome was decoded in 2003, researchers have been developing a powerful method for comparing the genomes of patients and healthy people, with the hope of pinpointing the DNA changes responsible for common diseases.

This method, called a genomewide association study, has proved technically successful despite many skeptics’ initial doubts. But it has been disappointing in that the kind of genetic variation it detects has turned out to explain surprisingly little of the genetic links to most diseases.

A set of commentaries in this week’s issue of The New England Journal of Medicine appears to be the first public attempt by scientists to make sense of this puzzling result.

One issue of debate among researchers is whether, despite the prospect of diminishing returns, to continue with the genomewide studies, which cost many millions of dollars apiece, or switch to a new approach like decoding the entire genomes of individual patients.

The unexpected impasse also affects companies that offer personal genomic information and that had assumed they could inform customers of their genetic risk for common diseases, based on researchers’ discoveries.

These companies are probably not performing any useful service at present, said David B. Goldstein, a Duke University geneticist who wrote one of the commentaries appearing in the journal.

“With only a few exceptions, what the genomics companies are doing right now is recreational genomics,” Dr. Goldstein said in an interview. “The information has little or in many cases no clinical relevance.”

Unlike the rare diseases caused by a change affecting only one gene, common diseases like cancer and diabetes are caused by a set of several genetic variations in each person. Since these common diseases generally strike later in life, after people have had children, the theory has been that natural selection is powerless to weed them out.

The problem addressed in the commentaries is that these diseases were expected to be promoted by genetic variations that are common in the population. More than 100 genomewide association studies, often involving thousands of patients in several countries, have now been completed for many diseases, and some common variants have been found. But in almost all cases they carry only a modest risk for the disease. Most of the genetic link to disease remains unexplained.

Dr. Goldstein argues that the genetic burden of common diseases must be mostly carried by large numbers of rare variants. In this theory, schizophrenia, say, would be caused by combinations of 1,000 rare genetic variants, not of 10 common genetic variants.

This would be bleak news for those who argue that the common variants detected so far, even if they explain only a small percentage of the risk, will nonetheless identify the biological pathways through which a disease emerges, and hence point to drugs that may correct the errant pathways. If hundreds of rare variants are involved in a disease, they may implicate too much of the body’s biochemistry to be useful.

Christopher Smith, great information. Would you please post or PM links to the sites where you have found this information. I find the genetics fascinating for this breed, and want to dig deeper in depth than what I have found so far.   Much appreciated.

I think that it depends on the disorder and the mode of inheritance.  Polygenic etc.  I can speak that the OFA database and genetic research in finding the the marker/gene for late onset PRA in ACDs has absolutely had an impact on the gene pool - for the good.  The national breed club voted to require that all PRCD tests submitted in the US be required to be published in OFA database.  When the marker test came out in May of 2002 the incidence of carriers/affected dogs was approximately 75%.  That rate has decreased significantly with the onset of the test and subsequent publishing on the results.  

But again, the mode of inheritance of the disease is understood and not complex.  For diseases like deafness and dysplasia it is not so clear cut.  With that said, I am someone who strongly advocates testing dogs and publishing results good and bad.  Whether someone chooses to use a dysplastic (for example) dog in their breeding program is their choice but at least you know what you are dealing with.  This article is primarily discussing human genome research which I think, while sometimes comparable to animals, can also be widely different as well.

Part of the problem lies in the presumption that heterosis translates to inherently healthier, which is not necessarily true even in a majority sense, and the standard notions of quantitatively measuring a population's genetic makeup are inherently with fault.  Adding to that, is the lack of consideration of gene environment correlation.

Rather, we generally speak of, heritability, which is roughly the phenotypic variation attributable to genotypic variation within a population. Heritability is further divided into "broad sense" (additive + dominance effects) and "narrow sense" (additive) flavors.¹ But the story doesn't end there as those who are skeptical of claims of heritability would remind you, there are gene-environment interactions (or correlation) as well as epistatic effects (the influence that loci have upon each other, adding a nonadditive factor in the equation). So, the final phenotypic variation in a population can be modeled like so....

V_p = V_a + V_d + V_i + V_ge + V_e

[V_i is epistatic variance, the others are self-evident]

http://www.gnxp.com/MT2/archives/003642.html

Humans likely contribute to their own diseases and conteract their own diseases on a much greater level than genes can counteract, I think. (my kids could spell psychoneuroimmunology in grade two, LOL!)  I don\'t quite think the OFA/genetic link can be that easily extrapolated from that study, unfortunately.

I do think I would like to see a study showing whether or not breeding within specific hip scores translated into breed improvements in that area, however

There's more current data on the gsd as a breed, but here's what's up to 2004...

When breeding hip scores to hip scores...

And a more simplified version...

Same data, different take...

Wow! Daryl - that's wonderful!~  Thank you!

I guess that definitively answers Christopher Smith's pondering over the OFA and genetics.  Seems there's not much of a question. 

HEY all the X rays in the last 30 oddddddddd years and we stilllll have hip problems ......... DUHhhhhhhhhhh<<<<<<<<<<<<< Crap shooooooooot yessssss AT BEST ....

Yeah, but only 4 % when excellent hip scores are bred to excellent hip scores.  That's a significant reduction from the other scores.