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I have followed medical science advances in treatment of cancer and multiple sclerosis. People that I care about have those diseases. You all have loved ones affected by those diseases. I have been deeply into it for three years. My wife died last year about battle with a rare devastating cancer. I became fascinated by the use of genetics to create a vaccine. The research on cancer stem cells was encouraging. But today I read a paper in The New England Journal of Medicine (NEJM) by David B. Goldstein, Ph.D. of Duke University that has me wondering: Common Genetic Variation and Human Traits

His concern is that our ability to understand a few of the genetic aspects of a disease is meaningless in coming up with treatment (drug) because the disease is caused by literally thousands of variations or genetic defects:

The human genome has been cracked wide open in recent years and is spilling many of its secrets. More than 100 genomewide association studies have been conducted for scores of human diseases, identifying hundreds of polymorphisms that are widely seen to influence disease risk. After many years in which the study of complex human traits was mired in false claims and methodologic inconsistencies, genomics has brought not only comprehensive representation of common variation but also welcome rigor in the interpretation of statistical evidence. Researchers now know how to properly account for most of the multiple hypothesis testing involved in mining the genome for associations, and most reported associations reflect real biologic causation. But do they matter?

Unfortunately, most common gene variants that are implicated by such studies are responsible for only a small fraction of the genetic variation that we know exists. This observation is particularly troubling because the studies are largely comprehensive in terms of common single-nucleotide polymorphisms (SNPs), the genomic markers that are genotyped and with which disease associations are tested. We’re finding the biggest effects that exist for this class of genetic variant, and common variation is packing much less of a phenotypic punch than expected.

The current research path is long in time and expensive in terms of research money. His conclusion is that the current process will not produce treatments and that a new approach is necessary.

The apparently modest effect of common variation on most human diseases and related traits probably reflects the efficiency of natural selection in prohibiting increases in disease-associated variants in the population. I believe attention should shift from genome scans of ever larger samples to studies of rarer variants of larger effect. Effectively searching the full human genome for rare variants will require not only sequencing capacity but also thoughtful selection of the most appropriate groups of individual genomes to resequence and thoughtful evaluation and prioritization of the many rare variants identified. There’s no guarantee that associations with rare variants will point directly to causation. Nevertheless, the limited role of common variation in many highly heritable diseases argues strongly that there are many rare variants to be found, and it seems reasonable to hope that some of them will suggest novel therapeutic targets or help in the design of personalized prevention or treatment regimens.

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.

Ken Cedeno, reporter for the New York Times has written an excellent review of the debate about which path to pursue in disease research.

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.

This debate is also important to companies that intend to make profits by selling personal genomic information people about their genetic risk for common diseases. To do that requires continued research on the current path. Dr. Goldstein would abort that avenue of research and foil that business model. The research either way it goes is very expensive.

“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.”

Only a few unusual diseases result from change to a single gene. 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.

As the New York Times story explains:

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.

The genetic changes identified so far in the traditional model have been thought to at least identify the pathways through which a disease emerges, allowing scientists to create drugs that may "correct the errant pathways". However if Goldstein is right and hundreds of rare genetic changes are involved in a disease, too much of the body’s biochemistry is involved to maker this a practical way to design drugs for common diseases to be useful.

“In pointing at everything,” Dr. Goldstein writes in the journal, “genetics would point at nothing.”

Agreeing with Dr. Goldstein that probably many genetic variants, rather than few, “are responsible for the majority of the inherited risk of each common disease, geneticists Peter Kraft and David J. Hunter of the Harvard School of Public Health, also writing in the journal, largely agree with Dr. Goldstein but disagree that there will be diminishing returns from more genomewide association studies.

“There will be more common variants to find,” Dr. Hunter said. “It would be unfortunate if we gave up now.”

Dr. Goldstein, however, said resources should be switched away from these highly expensive studies, which in his view have now done their job.

“If you ask what is the fastest way for us to make progress in genetics that is clinically helpful,” he said, “I am absolutely certain it is to marshal our resources to interrogate full genomes, not in fine-tuning our analyses of common variations.”

He advocates decoding the full DNA of carefully selected patients.

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