Newswise — Although it's our most vital organ, surprisingly little is known about what constitutes a "normal" brain. That makes it harder to uncover what's gone awry in people suffering from mental illness and other brain-associated disorders, and ultimately, it often leaves physicians treating symptoms rather than causes of conditions such as Alzheimer's and Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder (ADHD), and many other ailments.
That's why researchers from two San Antonio institutions have combined forces for the largest study of its kind to map out normal variations in brain structure and function and identify the genes responsible for those variations. They expect their five-year investigation " funded with two new cooperative grants totaling $7 million from the National Institute of Mental Health " to yield a host of new data on basic brain biology and mental illnesses, as well as spawn additional studies focusing on specific diseases.
Why study what's "normal" ?
Because scientists have not developed a good understanding of basic brain biology and the role of genes, they do not know the root causes of most mental disorders, said geneticist John Blangero, Ph.D., of the Southwest Foundation for Biomedical Research, who is leading the study with David Glahn, Ph.D., psychologist and associate professor at the University of Texas Health Science Center at San Antonio.
To get to the heart of the matter, Blangero and Glahn are taking a different approach from many previous studies of the brain. Rather than looking for research subjects suffering from a particular mental illness and studying differences in their brain structure and function, this research team is working with large family groups from the average population to better understand normal brain variation and the genes that control it.
"We want to inform aspects of brain biology that are relevant for a lot of different diseases," Blangero said. "That's why we're not focused on any disease. We're focused on finding the genes that influence normal brain variation. Those are going to be the same genes that also influence pathological variations."
"This gives us the potential to evolve some of the basic questions that we're constantly dealing with from the side of neurologic and psychiatric illness, research areas where it's difficult to gain traction when you're focused on the disease itself," explained Glahn. "This is because the things we're interested in -- be they cognition, brain structure or brain physiology " are changed dramatically in people with mental illness. So we [in the psychiatric community] are constantly questioning, 'Is this change [in the brain] a cause of the illness? A result of the illness? A result of treatment of the illness?' By studying the biology of the brain in healthy subjects, we'll be able to overcome the 'chicken-and-egg' problem that's constantly there in clinical research."
Potential impact
Glahn added that this study "allows us to potentially set the benchmark for which we can compare other studies that are more focused on individual diseases. We hope it will be the kind of study that will be the basis for a kind of next generation of psychiatric and neurologic genetic studies."
Its focus on genetic contributions to brain structure and function also should enable scientists to get to the underlying causes of mental disorders, and to develop better therapies.
"When we find a gene [that influences changes in the brain], that gene will immediately take us into the biology that isn't there now," Blangero said. "So, in terms of a discovery project, discovering a gene that's involved in brain function has potentially enormous ramifications for many areas of health. It immediately becomes a target for drug development, and it clarifies the nature of the underlying causal pathway [of a disorder], which in many cases we don't currently know."
That will help the medical profession to move beyond relying on drugs that treat symptoms, rather than causes, of brain disorders, Blangero added.
The San Antonio advantage
Both scientists point out that San Antonio is one of the few places this type of groundbreaking study can be conducted because of the unique combination of resources and expertise developed at Southwest Foundation for Biomedical Research (SFBR) and the University of Texas Health Science Center at San Antonio (UTHSCSA), as well as previous funding commitments to these resources by the National Institutes of Health, the State of Texas, private industry, and generous donors.
For example, research subjects for the study will be drawn from the San Antonio Family Heart Study, a long-term study funded by the NIH to find genes influencing risk for heart disease, diabetes and obesity. Led by SFBR geneticists with the support of investigators at UTHSCSA, the study includes 1,400 Mexican Americans from 40 San Antonio families, making it one of the largest family-based human studies known, offering tremendous potential for genetic discovery. For the past 15 years, participants have provided health and demographic information, undergone periodic physical examinations and provided blood samples for this extensive genetic investigation.
Now 1,000 members of that group will be recalled to undergo cognitive testing and have images of their brains taken with the advanced MRI equipment at UTHSCSA's Research Imaging Center. Directed by Peter Fox, M.D., who is offering valuable support to this new investigation, the center offers tremendous expertise and the latest in state-of-the-art imaging equipment that "lend a level of sophistication to this study that wouldn't otherwise be possible," said Glahn. "The amount of data that's generated from an image is just amazing. We routinely get about 150,000 variables."
Glahn's part of the research team will analyze the cognitive information and the brain images to sort out data relevant for Blangero's group at SFBR to search for genes related to normal brain variations.
At SFBR, home to one of the leading genetics groups in the world for large family-based studies, Blangero will use the novel statistical methods developed by him and his peers along with the world's largest computing cluster for genetic analysis " housed in the AT&T Genomics Computing Center " to sift through the vast amounts of research data and search for the genes influencing various aspects of brain structure and function. That work will be followed up by genetic sequencing studies in SFBR's molecular high-throughput laboratories, where scientists hope to identify the variations within those genes that are responsible for their varied effects.
"This study is truly the perfect marriage of our two institutions," said Blangero in describing the collaboration between SFBR and UTHSCSA. "By combining our resources and expertise, we're able to do something that could be done in few other places in the world. The result should be a major leap forward in scientific efforts to understand and better treat mental health problems."
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