As part of a five-year study, researchers at Texas Scottish Rite Hospital for Children identified new genetic markers for idiopathic scoliosis that highlighted two genes: CHL1 and DSCAM. These genes play a role in the neurologic and spinal systems. The research team was led by Carol Wise, PhD, director of molecular genetics at TSRHC. Swarkar Sharma, PhD, was the lead author of the study and is a postdoctoral fellow working with Dr. Wise. The article describing the team's research appeared in the April 2011 issue of the Human Molecular Genetics journal.
Dr. Wise discusses her team's discovery and where the field of genetic research associated with scoliosis is headed.
How the project began
The researchers involved in this project chose to focus on the genetic patterns associated with scoliosis because, in their view, this was how they could elucidate why adolescent scoliosis occurs. The team spent almost 15 years recruiting families into their studies to collect clinical and genetic information. "We put a big collection of those families together and posed the question: What is genetically similar between these patients?" says Dr. Wise. "We are looking for genetic markers that are shared among patients more often than you see in a control population."
Once the team gathered the genetic information from 419 families participating in the study, an analysis was taken to detect which markers are over-represented (or under-represented) in individuals with idiopathic scoliosis. There are approximately 350,000 genetic markers per person, which meant the team looked at a fairly high density of information across the genome. "We rank all of the markers and see which ones are highly significant and which are not," she says. "In our study, the most highly ranked markers were pointing to specific genes. Then we began looking at a larger scale and our question became this: If we examine other populations of patients, are we able to replicate these results?" The project was expanded to examine three different populations around the country, and the results were replicated in two of the three, giving the researchers confidence in the initial observation.
Connecting the genes with the biology
Once the relevant genes were identified, the researchers examined whether they were plausible candidates to denote the biology of the disease. In this case, there were two genes that were very plausible, while others still require further study before pushing forward with the next step in the process. "For the top two genes, we noticed right away that they participated in nerve growth," says Dr. Wise. "These genes tell the nerves in the spinal cord how to grow — whether they should grow up or down, left or right. There are very complex mechanisms that tell the nerves how to do that, and these genes participate in that process."
In some cases, rare diseases that involve scoliosis are caused by dysfunction in the nerve pathway. Among scoliosis surgeons and researchers, there has long been a suspicion that neurologic pathologies were involved in determining severe scoliosis, but the solid evidence was lacking. "There has never been a direct connection between a neurologic case and scoliosis," says Dr. Wise. "In the non-scoliosis research world, most people see it as a bone disease because that's how we treat it. We can now say is that our research suggests that the pathology of the nerves is a significant part of the disease."
What these discoveries mean for the future
As any scientist or researcher would point out, this study is an association study and association isn't always causation. However, the study has influenced the researchers' perspective about what can be causal. "We have to drill down to the actual changes and see what the functional result is," says Dr. Wise. "That will involve genetic and cell-based studies. But now, we can focus specifically on specific neurological and biochemical pathways. We have a place to focus and develop new hypotheses and test these hypotheses."
These findings won't change scoliosis detection or treatment in the near future, but over the next five years it will change how the disorder is monitored. Depending on what researchers are able to glean from the data during that time, they could develop new ways to monitor nerve development associated with scoliosis. "We don't know the exact implications of our findings at this point, but this is certainly an area we are investigating," says Dr. Wise.
Genetic scoliosis research group
The next several years will likely spur a plethora of discoveries in genetic research as it pertains to scoliosis. Technology and data input capabilities have developed to the point where researchers can potentially identify all genes that are relevant to the disease. The potential findings from this research could mean positive changes for treating a disease that currently takes a great deal of time and costs billions of healthcare dollars each year — not to mention the traumatic nature of invasive surgery for patients who don't respond to conservative management (observation or bracing).
"The new technologies emerging on the horizon are bringing people together," says Dr. Wise. "We are in the process of developing a scoliosis genetic research group, which is now formalizing meetings. We are hoping we can come together and produce some really large scale research on genetics in scoliosis. It's very important to share the knowledge and grow the knowledge we have together."
Dr. Wise is among the leaders who are spearheading the efforts to create a genetic scoliosis research group. She anticipates this group will help to stimulate international collaboration between researchers in countries such as China, the U.S., France, the United Kingdom and Russia, among others.
Related Articles on Scoliosis:
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Performing Minimally Invasive Surgery for Adult Scoliosis: Q&A With Dr. Neel Anand of Cedars-Sinai Medical Center in Los Angeles
How the project began
The researchers involved in this project chose to focus on the genetic patterns associated with scoliosis because, in their view, this was how they could elucidate why adolescent scoliosis occurs. The team spent almost 15 years recruiting families into their studies to collect clinical and genetic information. "We put a big collection of those families together and posed the question: What is genetically similar between these patients?" says Dr. Wise. "We are looking for genetic markers that are shared among patients more often than you see in a control population."
Once the team gathered the genetic information from 419 families participating in the study, an analysis was taken to detect which markers are over-represented (or under-represented) in individuals with idiopathic scoliosis. There are approximately 350,000 genetic markers per person, which meant the team looked at a fairly high density of information across the genome. "We rank all of the markers and see which ones are highly significant and which are not," she says. "In our study, the most highly ranked markers were pointing to specific genes. Then we began looking at a larger scale and our question became this: If we examine other populations of patients, are we able to replicate these results?" The project was expanded to examine three different populations around the country, and the results were replicated in two of the three, giving the researchers confidence in the initial observation.
Connecting the genes with the biology
Once the relevant genes were identified, the researchers examined whether they were plausible candidates to denote the biology of the disease. In this case, there were two genes that were very plausible, while others still require further study before pushing forward with the next step in the process. "For the top two genes, we noticed right away that they participated in nerve growth," says Dr. Wise. "These genes tell the nerves in the spinal cord how to grow — whether they should grow up or down, left or right. There are very complex mechanisms that tell the nerves how to do that, and these genes participate in that process."
In some cases, rare diseases that involve scoliosis are caused by dysfunction in the nerve pathway. Among scoliosis surgeons and researchers, there has long been a suspicion that neurologic pathologies were involved in determining severe scoliosis, but the solid evidence was lacking. "There has never been a direct connection between a neurologic case and scoliosis," says Dr. Wise. "In the non-scoliosis research world, most people see it as a bone disease because that's how we treat it. We can now say is that our research suggests that the pathology of the nerves is a significant part of the disease."
What these discoveries mean for the future
As any scientist or researcher would point out, this study is an association study and association isn't always causation. However, the study has influenced the researchers' perspective about what can be causal. "We have to drill down to the actual changes and see what the functional result is," says Dr. Wise. "That will involve genetic and cell-based studies. But now, we can focus specifically on specific neurological and biochemical pathways. We have a place to focus and develop new hypotheses and test these hypotheses."
These findings won't change scoliosis detection or treatment in the near future, but over the next five years it will change how the disorder is monitored. Depending on what researchers are able to glean from the data during that time, they could develop new ways to monitor nerve development associated with scoliosis. "We don't know the exact implications of our findings at this point, but this is certainly an area we are investigating," says Dr. Wise.
Genetic scoliosis research group
The next several years will likely spur a plethora of discoveries in genetic research as it pertains to scoliosis. Technology and data input capabilities have developed to the point where researchers can potentially identify all genes that are relevant to the disease. The potential findings from this research could mean positive changes for treating a disease that currently takes a great deal of time and costs billions of healthcare dollars each year — not to mention the traumatic nature of invasive surgery for patients who don't respond to conservative management (observation or bracing).
"The new technologies emerging on the horizon are bringing people together," says Dr. Wise. "We are in the process of developing a scoliosis genetic research group, which is now formalizing meetings. We are hoping we can come together and produce some really large scale research on genetics in scoliosis. It's very important to share the knowledge and grow the knowledge we have together."
Dr. Wise is among the leaders who are spearheading the efforts to create a genetic scoliosis research group. She anticipates this group will help to stimulate international collaboration between researchers in countries such as China, the U.S., France, the United Kingdom and Russia, among others.
Related Articles on Scoliosis:
Improving Scoliosis Treatment: Q&A With Vincent Artlet, Developer of Scolisoft Scoliosis Database
Dr. Robert Rovner: 3 points on a New Technique for Better Outcomes in Scoliosis Surgery
Performing Minimally Invasive Surgery for Adult Scoliosis: Q&A With Dr. Neel Anand of Cedars-Sinai Medical Center in Los Angeles