Search Widens for Causes of Psychiatric Disorder

by Kayt Sukel

February 25, 2009

Despite the recent leaps in our knowledge concerning the human genome, research in this area has not yet provided the kind of concrete answers that physicians and their patients had long hoped for. An emerging discipline, epigenetics, may—and may offer new directions for research as well as more targeted therapies for treatment.

More than the sum of our genes

Simply defined, epigenetics means “in addition to” genetics. It is the study of heritable changes in gene expression caused by nongenetic factors.

Scientists have long known that some complex psychiatric disorders can be passed from generation to generation. From Huntington’s disease to schizophrenia, a parent’s diagnosis increases the likelihood that any offspring will also develop it.

“We know you can take a child from schizophrenic parents, and even when that child is adopted by normal parents and raised in a normal family environment, that child still has a 50/50 chance of coming down with the disorder,” says Eric Kandel, a Nobel Prize–winning scientist at Columbia University and an executive committee member of the Dana Alliance for Brain Initiatives. “But a child with two normal parents has less than a 1 percent chance of developing schizophrenia.”

These observations led the scientific community to seek genetic precursors for many of these diseases. Timothy Trull, a psychology researcher at the University of Missouri, Columbia, has been searching for potential gene candidates for borderline personality disorder (BPD), a psychiatric disorder characterized by severe instability in moods, interpersonal relationships, self-image and behavior.

“We knew that BPD was partially heritable,” says Trull. “But the next step was to figure out just what was inherited, what genetic mechanism might be responsible.”

In a study published in the December 2008 issue of Psychiatric Genetics, Trull and colleagues at VU University Amsterdam published the results of a genetic linkage study that associated a specific region on chromosome 9, previously linked to emotional dysregulation in bipolar patients, with BPD. But because BPD is only a “partly heritable” disorder—it has been associated with several environmental factors—Trull says he will also look more closely at how genes of interest may be turned on or off by factors such as a traumatic childhood or drug abuse.

“Understanding these gene-by-environment interactions provides us an even more comprehensive picture of how these diseases develop,” he says. “It opens up a wide range of possible interventions, both in terms of prevention and treatment if it has already manifested.”

Taking a wider look

“Disorders like schizophrenia or Alzheimer’s disease are complex ones,” says Hongjun Song, a neuroscientist at the Johns Hopkins University School of Medicine. “It’s unlikely that these are single-gene cases, or some master gene disrupted to some degree.”

Some researchers argue that complex psychiatric disorders are never caused by single genes, but rather by sets of genes across the genome that are defective and do not copy themselves correctly. This approach, termed copy number variation, suggests that the duplication or deletion of chromosomes across the genome may contribute to these pathologies.

“Copy number variation is fast becoming a powerful theme,” says Kandel. “Often the mother doesn’t have the disease, the father doesn’t have the disease, and the sibling doesn’t either—just the affected individual, and yet we know that it is a genetic disease. How do you explain that? It turns out that this is what is called a de novo mutation, a mutation in the sperm or egg, and many of these result in copy number variations. This has many implications for the way we look at these diseases.”

Stephen Faraone, the director of medical genetics research at the State University of New York Upstate Medical University, is studying gene-environment interactions for another complex disorder, attention-deficit/hyperactivity disorder (ADHD).

“We look at ADHD from multiple angles. We know that there is a genetic component that is heritable,” Faraone says. “But we also know from animal models and epidemiological studies that environmental exposures like pregnancy and delivery complications also play a role.”

Faraone’s lab is looking for potential gene targets in genome-wide association studies and working with animal models to see how environmental exposures may alter gene expression in brain areas associated with ADHD.

“You have to approach these kinds of disorders from a big-picture perspective,” he says. “There’s the human component, the results from human epidemiological studies, animal models and gene identification. Looking at these epigenetic effects gives us the opportunity to look into the petri dish and try to identify new pathways that may be involved in the kinds of dysregulation associated with ADHD.” And that, he argues, may yield targets for the development of more effective drugs with fewer side effects, as well as changing environmental behaviors to prevent disease.

At the door to a new field

Researchers have only begun to define and refine epigenetic methods. To truly understand the cellular mechanisms underlying gene-environment interactions, they first needs to pinpoint the affected genes—a task requiring large sample sizes and a lot of lab work—as well as potentially very subtle environmental factors that may also be playing a role.

“We’re trying to find normal ways to understand the system. But we have to look beyond just what environmental factors turn a gene on and off,” says Song. “We also need to look at different time scales, how these changes are sustained and what controls those sustained changes, too.”

Kandel thinks that we will soon have a much deeper understanding of what is happening at the molecular level when it comes to complex psychiatric disorders. “With so many disorders, I believe that we’ll soon see that you don’t permanently screw up the development of the nervous system or have ongoing damage to the nervous system,” he says. “Instead, it’s possible that once you understand the glitch, you can turn it off and reverse the bad stuff.”

Faraone agrees. “I do believe that in the next five years we’ll see some amazing breakthroughs in the neurobiology of ADHD and other complex disorders,” he says. “It is an exciting time to be keeping track of this.”

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