New England Journal of Medicine Opinion Papers on Genes and Disease: Analysis and Implications for PD Genetics Research
On April 15 opinion papers published in the New England Journal of Medicine (NEJM) received worldwide press for their position statements on genes' limited ability to predict human disease. Brian Fiske, PhD, MJFF's associate director, team leader, research programs, provides analysis of the papers and their implications for ongoing research into the genetics of Parkinson's disease.
Q: Newspaper articles and the NEJM papers themselves seem to say that genes are not that useful in predicting disease. Are the authors saying that research into the genetics of PD is no longer useful?
BF: No. Genetics research, in Parkinson's as well as other diseases, continues to move forward, actually faster than ever. These papers argue -- rightly, I believe -- that new progress will ultimately require the development of next-generation techniques for peering even deeper into our DNA. This is how we will capture a more complete picture of how genes contribute to diseases like PD.
The papers are essentially the summation of a position that has been growing in popularity among researchers for some time now: The genetic basis of diseases like PD is extremely complex, and current genetic research methods must be augmented with new and more powerful technologies in order to explain the full genetic basis of disease. The techniques we've been able to use so far allowed us to look in some obvious places and identified a number of genetic changes linked to PD. But the genetic basis is still unclear for the vast majority of cases. And because we don't have a full understanding, it also makes it very difficult to make an accurate prediction of risk for getting PD even if you have PD-associated genetic changes.
Q: Does this mean genes don't have much to do with PD?
BF: No -- and this is a critical point. The scientists are not concluding that genetics plays no significant role in PD. They are saying that it's more complex than having a single genetic 'smoking gun.' More specifically, there is no clear, large and common genetic change that can explain the vast majority of PD cases in the world -- something we had already suspected for some time.
Q: But I keep hearing about genes that are linked to PD. So why don't we know more about the genetic aspects of the disease?
BF: That's true. But finding the specific gene changes that explain disease has not been easy. It may be helpful if we look at how we reached our current understanding, to help clarify what the new position means.
In the earliest days of genetic research, scientists studied rare families where disease was clearly being inherited from one generation to the next. In PD specifically, such studies led to the identification of a number of mutations that greatly increase risk for Parkinson's, such as those in the genes for alpha-synuclein and LRRK2.
A better method was needed to find genes that might contribute to disease in the general population (after all, the vast majority of PD cases are sporadic and do not have a clear pattern of inheritance). The completion of the Human Genome Project several years ago, and the full human sequence data that resulted from that effort, led to the development of technologies that enabled geneticists to conduct so-called genome-wide association (GWA) studies -- quickly scanning a person's DNA sequence to find special genetic 'landmarks' called single-nucleotide polymorphisms (SNPs). These changes in the DNA code allowed researchers to identify small regions of DNA that are 'associated' with a disease -- that is, found more frequently in people with a given disease than without. Once identified, the race would be on to clarify and refine which genetic change in that region was the real culprit.
GWA studies are a powerful technique, but they have a significant limitation: They can identify only SNPs that are fairly common. That's fine if the gene alterations involved in disease really are common to a lot of people. But if a disease is ultimately caused by many rare mutations found in relatively small groups of people -- as might be the case in PD -- the approach loses its advantage.
Q: So what are the technologies that we need to focus on now to make new progress?
BF: Several of the NEJM authors argue that we need to start thinking about the next wave of technology: full-genome sequencing.
A few years ago, it would take many labs and vast amounts of funding to sequence all the DNA letters of just a few individuals. But the technology is rapidly advancing. It is quite possible that within the next few years, the $1,000 genome sequence could be a reality. That will open the floodgates for new studies of the genetic basis of disease.
We're excited by the development of new and more powerful technologies. We're also enthusiastic about efforts to engage and educate patients on the genetics of PD, and to develop novel methods for the collection of data required if these technologies are to make practical contributions to therapeutic breakthroughs. Our work in this area includes our Web-based Clinical Assessments program and our partnership with The Parkinson's Institute and 23andMe.
Q: Can you explain how the combination of new research technologies and novel methods for collecting data from patients may open the floodgates?
BF: With a set of complete DNA sequences from multiple individuals, scientists can compare each letter in the code and find even rare mutations that would have been missed with previous GWA study methods. It is within these rare mutations that many scientists now think the key to understanding complex diseases truly lies. There is certainly still the risk that even if we go deeper, we may come up empty handed. If that happens, it will likely cause a major shift in our thinking about the causes of PD.
But even with identification of a more complete list of gene changes that contribute to disease, the real work comes in understanding how those changes ultimately lead to disease. Do they alter the levels of proteins in a cell or how they function? And what other genetic or even environmental factors might impact whether a particular genetic mutation actually causes disease or not? All of this requires not only the ability to look deeper in our DNA, but also to know more about people with PD and what defines their disease. From the angle of how to convert genetic findings into actual therapies, it is this understanding that is really important.
Q: What is The Michael J. Fox Foundation's position on genetics and PD?
BF: It's been our position for some time that GWA studies can only tell us so much about Parkinson's. In fact, based on results from the first GWA study for PD, which MJFF funded back in 2005, we have felt confident for a while that no single common variation in our DNA explains a large percentage of Parkinson's risk in the general population.
But we believe that as technology evolves and becomes more affordable, researchers will continue to identify new genetic variations that play a role in disease onset and progression. At the end of the day, it's really an issue of how can we capture all of the potential genetic changes that can cause or increase risk for PD. On top of all that, we still have a lot to learn about precisely how specific gene changes lead to disease, which is how you then learn to develop therapies.
Ultimately, MJFF believes that genetic research will be key to increasing human understanding of PD, and will play an important role in the development of breakthrough treatments.