The Genome Scan Debate

Science Magazine has published a brief but well written article on the debate about the use of genetic analysis in assessing the susceptibility to certain diseases. It states:

"In the most provocative of four NEJM articles, David B. Goldstein, director of the Center for Human Genome Variation at Duke University in Durham, North Carolina, says the first 100 or so genomewide association studies (GWAS), which use gene chips to f ind associations between common gene variants and diseases, have identified important variants that appear to influence disease risk, but the impact of most of those variants is relatively low. He told Science that, once such association studies “have been run on the first few thousand patients for a given disease, there is only marginal return in pushing the sample sizes up further.” Instead, he wants to shift more research to full sequencing of patients’ genomes to find “rarer variants of larger effect” linked to disease."

The article continues:

"Although it has become the focus of much public attention, predicting personal risk is not the point of GWAS, argues Joel N. Hirschhorn, a genomics researcher at the Broad Institute and Harvard University Medical School who wrote an NEJM commentary that offered a positive assessment of GWAS results. “The goal is not individual risk analysis but rather discovering the biological pathways underlying diseases,” he says."

As we have discussed before genetic techniques can serve in four areas; screening, staging, treatment, and prevention. The focus of this discussion is screening. I have had concerns about the overall view of this effort in that we already know that having a single aberrant gene is at best a mild predisposition. Take colon cancer for example. Since the work of Bert Vogelstein at Hopkins we know that colon cancer, and now many other cancers, result after multiple sequences of genetic hits on certain cells. There may be a body wide genetic predisposition but it is the ensuing hits on the genes as the cells reproduce that result in the problem. It is the pathway issue which are of concern. Thus having a specific gene may give you a 5% increase in risk. The reality is what happens to that 5% risk over time, does it change the cell into a cancer precursor? Cancer is a progressive genetic disease that allows for unbridled cell growth. The progress to cancer is a result of the cell shutting down its growth control mechanism.

The second issue is that of say Type 2 Diabetes. If one discovers a gene for Type 2 Diabetes then the question is is this a gene which allows for unstable weight growth, that per se causes diabetes, that works in some pathway manner to cycle up to diabetes. What is the overall process of type 2 Diabetes? One must look at this as a complex system not just as a single genetic hit.

Is this a problem for genetic testing? Hardly, this appears to be just another academic spat on the way to eventually seeing this holistically as a complex system.