Researchers recently broke new ground in finding the genetic causes of mental illness, identifying a specific region in the genome associated with schizophrenia, bipolar disorder, and autism.
An international team, led by geneticist Jonathan Sebat, Ph.D., of Cold Spring Harbor Laboratory, has discovered a mutation on human chromosome 16 that is a potent risk factor.
"This type of genetic variation is called copy number variation," Sebat explains. "It means that instead of having differences in sequence, you have a deletion or a duplication of a whole gene or genomic region. It's not a mutation; it's extra copies of a gene. So the dosage of the gene changes, rather than the sequence."
Specifically, Sebat and his team found that a duplication in copy number variation predisposes someone to schizophrenia and bipolar disorder - and a decrease in CNV is associated with autism.
"Basically, the implication is that the same gene is associated with multiple disorders," say Sebat. "The ways they're disrupted determines how they influence the long-term psychiatric outcome."
He cautions, "This is a slight oversimplification. There is fuzziness there. Duplication is also associated with autism. No matter how you mutate this region, you could get a child with autism or developmental delay. Any mutation in this region can result in a child with a developmental delay."
Others involved in the research include Deborah L. Levy of the Psychology Research Laboratory at McLean Hospital in Belmont, Massachusetts, and the Department of Psychiatry at Harvard Medical School in Boston, who was awarded a NARSAD Independent Investigator grant. The results of this study were published on the Nature Genetics website on October 25, 2009, prior to coming out in the journal.
Applying a New Approach
In their research, the team pioneered a new approach, using a technique called microarray analysis. "We used a gene chip to scan the genome," Sebat explains, "looking for sections that were increased or decreased in copy number. Early on, it became clear that this was an excellent tool for cataloguing the mutations found in anyone's genome.
"We uncovered a very important finding: that genetic risk factors for common neuropsychiatric disorders like schizophrenia and bipolar disorder are rare variants that are contributing to a common disease." He notes that both are common in terms of prevalence, with 1% of the population having schizophrenia and 1% having bipolar disorder.
Sebat adds, "We were testing a completely new hypothesis: Maybe a common disease is not a result of common genes, but of rare mutations - meaning they're different in every patient. This is a new approach."
Relating CNV to Physical Appearance
Another aspect of the research was identifying a clinical characteristic common to patients with these neuropsychiatric disorders. "We asked, ‘What aspect of the clinical data was consistent with the phenotype (physical appearance)?' " Sebat says. "We found one piece, and that was head size. There's a strong correlation of copy number with psychiatric outcome and also a correlation between copy number and head size. Deletion is associated with increased head size and duplication is associated with decreased head size."
He notes that while the research focused on chromosome 16, a second chromosome was also implicated. "On chromosome 1 you see the same thing: changes in copy number correlates with head size and with diagnosis," he explains. "On chromosome 1, the mutation that increases head size is associated with autism and the one that decreases head size is associated with schizophrenia." Deletions on chromosomes 15 and 22 have also been found to confer substantial risk of schizophrenia.
"Not only can we identify definite causes of schizophrenia," Sebat says, "but different studies have been able to reproduce our findings. All the studies find that the same loci are associated with these disorders. And they carry quite strong effects, increasing risk by a factor of 10.
"The headline news is that we can find the genetic causes of schizophrenia, which we hadn't been able to do for decades of trying," he concludes. "In just a few short years, we've been able to go from preliminary findings to very solid associations and right down to looking at clinical relevance - not just for schizophrenia but also for cognitive disorders."