In the past decade, there has been a shift in how researchers have approached the study of how genes affect disease. Before, many researchers hoped to find a single gene, or small group of genes, responsible for a disorder—an easy target for potential intervention. But as sample sizes in large-scale genome-wide association studies have gotten larger, geneticists are learning that dozens if not hundreds of genes may be significantly correlated with a single neuropsychiatric disease. This has led some researchers to argue that disorders like schizophrenia or autism are not single diseases but rather collections of multiple, different rare genetic disorders.
“Brain disorders are proving that what we’ve previous thought of as a common disorder is rather a collection of very rare and very different genetic mutations that may lead to similar symptoms or phenotypes,” says Huda Zoghbi, a professor in the departments of pediatrics, molecular and human genetics, and neurology at the Baylor College of Medicine. “We have learned that if you take a thousand patients with Alzheimer’s disease or Parkinson’s disease or autism, any one of those different diseases, one to ten of those patients may have a mutation on gene X. Maybe another ten will have some kind of mutation on gene Y, and so forth.”
This discovery, Zoghbi argues, is an opportunity for advances in treatment. “Genes don’t cause disease all by themselves. We need to understand the function of the proteins made by these genes as well as the pathways they work within,” she says. “At the end of the day, there are a few common pathways that will get you to these various disorders. And unless we understand them, we can’t find the best treatments.”
5 disorders, 4 common loci
One of those common pathways likely involves calcium channel signaling in brain cells. In a study published in The Lancet in late February, members of the international collaborative group the Psychiatric Genome Consortium put together a genetic data set of more than 60,000 individuals—some with psychiatric disorders, some without—to see if there were any common genetic denominators in schizophrenia, bipolar disorder, autism, major depression, and attention deficit hyperactivity disorder (ADHD). The consortium found four common risk loci—regions on chromosomes 3p21 and 10q24, as well as two genes involved in calcium channel signaling in neurons, CACNA1C, a gene previously linked to bipolar disorder and schizophrenia, and CACNB2.
“We also did a pathway analysis, which lets you look at the effect of genes grouped into biological pathways,” says Jordan Smoller, professor of psychiatry at Harvard Medical School and lead author on the study. “The pathways that emerged as associated with all five of these disorders was calcium channel signaling. It raises the hypothesis that genetic variation in certain brain systems or circuits may increase the susceptibility to a broad range of outcomes.”
Dennis Vitkup, a professor of biomedical informatics at Columbia University, says this makes sense. He and his colleagues had previously demonstrated that both schizophrenia and autism shared genetic mutations that affected common brain networks involved in axon guidance and synapse function. Their study was published in Nature Neuroscience in September 2012.
“We are seeing a lot of interesting genetic connections between diseases we may not have thought overlapped,” says Vitkup. “Our understanding of these diseases is coming full circle and there’s now convergent evidence that some of the same processes and networks are affected and may be important to understand how these different disorders develop.”
Informing diagnosis and treatment
Zoghbi, Smoller, and Vitkup think these kinds of genetic studies may point researchers in new directions for research, and help them develop better diagnostic criteria and treatments for brain disorders.
“Neurological and mental disorders are going to be about synaptic function. We know this. They’re going to be about failure of communications between brain cells,” says Zoghbi. “Think about the architecture of a synapse. There are maybe hundreds of ways you can change the architecture of the synapse. But as we learn more about these genes of interest, we may be able to determine what role those genes play in the architecture of the synapse, how they are changing it. We can look at how the environment may influence those genes to give you full-blown symptoms.”
Having that understanding, Vitkup argues, will change the way we diagnose psychiatric disorders. “Psychiatry currently diagnoses diseases by symptoms and history of the disease,” he says. “In a few years, we can be more precise. Instead of saying, ‘this person has schizophrenia,’ we can say, ‘this person has this particular pathway affected’ and come up with drugs that can target that pathway directly.”
Smoller is quick to point out that his study and others like it are first steps in a long road of discovery. Still, he is very optimistic—the genome consortium plans to expand its sample sizes and add in data on disorders like obsessive-compulsive disorder (OCD), Tourette’s syndrome, and post-traumatic stress disorder (PTSD). “Even if what we find only has a modest, individual risk, it points us to biology that we might not have been aware of before. Almost all of the available treatments for neuropsychiatric disorders, while they are helpful for many people, are based on biology we’ve known about for 40 or 50 years,” he says. “So I think this idea of calcium channel signaling as a common pathway is promising because it’s doing exactly what we hoped—giving us a window into a new biological pathway that we can study. And that may lead to treatments that are more specific and effective for people.”