More than a dozen genes have been linked with schizophrenia, and the
findings replicated, Daniel Weinberger, M.D., told Psychiatric News
recently. Weinberger is director of the Genes, Cognition, and Psychosis
Program at the National Institute of Mental Health.
Most of the genes, he explained, were identified via linkage analysis, in
which genes from family members with and without schizophrenia were compared.
However, he predicted that more genes underlying schizophrenia will probably
be identified once scientists start using a new technique called whole-genome
association (WGA). This allows a researcher to rapidly scan the entire genome
of individuals with schizophrenia, as well as of control subjects, for
particular snips of genetic material and then to compare results for the two
Indeed, it looks as if Weinberger's prediction is coming true. Todd Lencz,
Ph.D., of Zucker Hillside Hospital and the Feinstein Institute for Medical
Research in Glen Oaks, N.Y., and colleagues have used WGA to link yet another
gene to schizophrenia. They reported their finding in the March 20
Lencz and his colleagues deployed WGA to scan the entire genomes of 178
individuals with schizophrenia and 144 healthy control subjects for some
500,000 fragments of genetic material. They found that a particular fragment
was three times more common in the schizophrenia subjects than in the
controls. The fragment, called rs4129148, is located on both the X and Y
chromosomes and, most intriguingly, is located next to two genes known to make
receptors for cytokines. Cytokines are produced by cells for cell-to-cell
communication and are critical to the body's immune responses. Cytokine
abnormalities have been associated with some cancers and inflammatory
Thus, if rs4129148, like the genes next to it, makes a cytokine receptor,
it would implicate the immune system in schizophrenia. Many of the other genes
tied to schizophrenia, in contrast, seem to impact basic processes of brain
development such as neuronal differentiation and neuronal plasticity.
And if rs4129148 makes a cytokine receptor, it might explain some of the
putative environmental inputs into schizophrenia, Lencz and his group
For instance, well-replicated findings of heightened schizophrenia risk for
winter-born and urban-born-or-dwelling persons, combined with large studies
demonstrating increased schizophrenia risk following maternal exposure to
various infectious pathogens, suggest that prenatal infection is a potent
environmental risk factor for schizophrenia.
But simply being exposed to a prenatal infection may not be sufficient to
trigger schizophrenia; susceptibility genes that allow infectious agents to
damage the brain may also be involved. And one of these susceptibility genes
may be rs4129148.
Or as Anil Malhotra, M.D., the study's senior investigator, pointed out in
a press release, "A role for cytokines could help explain why prenatal
exposure to viruses is a risk factor for schizophrenia, thus providing a
bridge between genetic risk and environmental exposures." Malhotra, like
Lencz, is affiliated with Zucker Hillside and the Feinstein research
Still other evidence underscores the possibility that schizophrenia may be,
at least in part, an illness of a cytokine system gone awry. For example,
abnormally high levels of pro-inflammatory cytokines have been found in the
blood and cerebrospinal fluid of individuals with schizophrenia.
"As with any genetic-association study, additional independent
replications from other laboratories will be critical to confirm these novel
findings," Lencz and colleagues concluded.
The research was funded by the Donald and Barbara Zucker Foundation,
KeySpan Energy, the National Institute of Mental Health, NARSAD, the Mental
Health Research Association, and the Stanley Medical Research Institute.
"Converging Evidence for a Pseudoautosomal Cytokine Receptor
Gene Locus in Schizophrenia" is posted at<www.nature.com/mp/journal/vaop/ncurrent/index.html>.▪