Chunks of DNA fragments that are scattered throughout chromosomes and
sometimes mess up functional gene sequences may in part explain the
development of schizophrenia and other neuropsychiatric disorders, according
to new research produced independently by two groups of
Two studies in different patient populations were combined into one paper
and published online in Science on March 27.
A group of National Institute of Mental Health (NIMH) researchers, led by
Anjene Addington, Ph.D., and Judith Rapoport, M.D., found that 28 percent of
patients with childhood-onset schizophrenia (COS) carried certain rare
structural variants that disrupted normal genes. Similarly, researchers from
Cold Spring Harbor Laboratory and the University of Washington, led by
Jonathan Sebat, Ph.D., and Jon McClellan, M.D., found that 15 percent of
patients with the classic type of schizophrenia carried rare structural
variants in their genomes. Among patients with classic schizophrenia, 20
percent of those with an onset before age 18 carried rare structural variants.
In contrast, only 5 percent of healthy, unrelated controls had these
Structural variations or mutations refer to chunks of repeated or missing
DNA sequences (that is, microduplications and microdeletions, respectively)
throughout a chromosome. Such variations may arise from mistakes during
replication or chromosome misalignment during the development of sperm or
eggs. Some of these mutations, also known as copy number variations, are
common to all or most people. Certain rare variations have been linked to
The researchers systematically scanned and compared the genomes of
schizophrenia patients and of healthy controls, and of COS patients and their
healthy parents to identify rare structural variations that were more frequent
in patients with the disorder.
The genes disrupted by rare structural variants associated with
schizophrenia were concentrated in brain-development pathways. For example,
one of the genes disrupted, SLC1A3, codes for a glutamate transporter protein
found in many synapses in the brain. Transcription from these genes may be
defective, or the protein produced may be dysfunctional because of the random
deletion or duplication of DNA sections.
To further complicate the picture, "virtually every rare structural
mutation detected in our [study] was different," the authors wrote.
Scientists have been searching for a few common genetic mutations in patients
with schizophrenia with a focus on common mutations within the suspect genes
themselves, but so far have been unable to find "the smoking gun."
Many genes seem to be involved in the disease but none has a large
The new findings "suggest a new model for finding new genes and
mechanisms," Rapoport, a senior investigator and child psychiatrist at
NIMH, told Psychiatric News. Each specific mutation was rare by
itself, and many were confined to one family or a single patient. In other
words, patients with the same clinical diagnoses have different mutations that
affect different genes on different chromosomes. Collectively, however, they
are associated with a substantial proportion of schizophrenia patients.
"It means that there are different ways to disrupt the same
neurological pathway and that there are different pathways to
schizophrenia," commented Rapoport. She noted that the COS patients
studied by her group had a higher likelihood of carrying these rare structural
mutations than did the classic schizophrenia cohort, probably because the COS
patients are a more homogeneous group. COS is a rare and severe form of the
disease with an onset before age 13.
Most of the rare mutations identified in the COS patients were inherited
from their healthy parents, which adds to the mystery. "[The mutations]
are risk factors, but they are neither necessary nor sufficient for developing
schizophrenia," she said. Structural mutations may also occur
This type of genetic variations throughout chromosomes may be a lot more
important to disease pathology than previously expected. In a study published
in the April 20, 2007, Science, Jonathan Sebat and colleagues linked
the same type of structural mutations to autism spectrum disorders. The number
of genes disrupted by these mutations and the signaling pathways affected by
these disrupted genes may be staggering.
In the current study, a particular microdeletion and a microduplication
identified in several COS patients in the study had previously been linked to
autism, mental retardation, and bipolar disorder. All this evidence seems to
suggest that one psychiatric disorder in different patients may originate from
a variety of genetic mutations in a complex web of pathways during brain
development, and different disorders may share some of the same mutations and
pathways. "Anyone in the [schizophrenia genetics] research knows that
the reality is exponentially more complicated than what we already
know," Rapoport said.
An abstract of "Rare Structural Variants Disrupt Multiple
Genes in Neuro-developmental Pathways in Schizophrenia" is posted at<www.sciencemag.org/cgi/content/abstract/1155174>.▪