Collaborations yield new discoveries in psychiatric genetics

Two New Jersey research teams are reporting discoveries about the biological nature of psychiatric disorders that may bring them closer to the ultimate goal of finding cures for complex diseases, such as autism and schizophrenia.

Scientists at Rutgers, The State University of New Jersey, in collaboration with colleagues at the University of Medicine and Dentistry of New Jersey (UMDNJ) have unveiled new information regarding the genetic, cellular and neurological bases of susceptibility to these diseases.

Using data drawn from the Rutgers Cell and DNA Repository on 518 families, each with multiple autistic children, James Millonig and Linda Brzustowicz, assisted by Emanuel DiCicco-Bloom, led a team that further substantiates the link between autism and Engrailed 2 (EN2), a gene important in central nervous system development. Their research is presented in the November issue of the American Journal of Human Genetics (AJHG).

Millonig and Brzustowicz had previously demonstrated an association with the gene in a sample of 167 families with autism. The new study adds another 351 families and now provides convincing statistical support for the existence of a mutated form of EN2 that increases the risk for autism. The statistics also showed EN2 may contribute to up to 40 percent of autism cases in the general population.

EN2 is involved with the development of the cerebellum, the part of the brain that governs movement and, to some extent, language and speech. A change in EN2 could potentially produce symptoms of autism. Further work on characterizing EN2 and on the identification of additional autism susceptibility genes will be funded by a $2.3 million grant to Millonig and DiCicco-Bloom and a linked $2.5 million grant to Brzustowicz from the National Institute of Mental Health (NIMH) to identify additional autism susceptibility genes.

Millonig is an assistant professor of neuroscience and cell biology at UMDNJ-Robert Wood Johnson Medical School (RWJMS) and an adjunct assistant professor in Rutgers’ department of genetics. He is also a resident faculty member of the Center for Advanced Biotechnology and Medicine, a research enterprise jointly operated by both institutions. Brustowicz is a professor of genetics at Rutgers, a board certified psychiatrist and an associate professor of psychiatry at the UMDNJ-New Jersey Medical School; DiCicco-Bloom is a professor of neuroscience and cell biology at UMDNJ-RWJMS.

A second team led by Brustowicz and Bonnie Firestein, an assistant professor in Rutgers’ department of cell biology and neuroscience, implicated a gene called CAPON in schizophrenia. A report of their research is available in the online journal PLoS (Public Library of Science) Medicine.

CAPON had been previously identified as a gene involved in the processes of communication between neurons in the brain. The Rutgers team identified a new variant of the CAPON gene that produces a shorter protein product. Using a sample of post-mortem brains, the researchers found elevated levels of this variant in the brains from individuals with schizophrenia and bipolar disorder. Brzustowicz and Firestein also offered their conclusions about how CAPON operates in its signaling context, functional evidence supporting the connection between the gene and these psychiatric diseases.

Researchers agree that there are environmental contributors to susceptibility to psychiatric disorders, but based on inheritance patterns of these diseases seen in families, the genetic component appears to be quite strong. The inheritance picture, however, is far from clear. It is not like the simple, one-gene models for eye color or blood type or found in such diseases as muscular dystrophy or cystic fibrosis.

“The diseases we study are polygenic, meaning that many genes are likely to contribute, but how many genes there are and how they interact are unknowns,” Millonig said. “Identifying a gene in a complex disease may give more insight into the pathways involved – it helps you begin to unravel what is at its basis.”

Earlier genetic studies of a Canadian study population of large families with a high incidence of schizophrenia pointed the way to CAPON. The gene was known to code for a protein that functioned in a neuronal pathway thought to be linked to schizophrenia. Beyond establishing a mere statistical connection between a gene and a psychiatric disorder – CAPON and schizophrenia – Firestein and Brzustowicz provided functional evidence as to the nature of the connection. “We began with a purely genetic approach and identified a region of chromosome 1 that seemed very likely to contain a susceptibility gene, but then moved on to studies of gene expression in human brains to search for convincing evidence of a functional role for CAPON in schizophrenia,” Brzustowicz said.

The researchers discovered two forms of the gene are normally expressed in human brain, a long form and a short form. Based on what is known about the gene interactions, it is predicted that when the short form is present in excess, it will disrupt the signaling pathway, resulting in decreased function, reduced signaling and less communication, all of which are suspected to occur in schizophrenia, Firestein said. The published information includes a detailed description of how this is thought to occur.

The research team then analyzed the post-mortem brains – 35 from individuals with schizophrenia, 35 from bipolar individuals and 35 from those with normal brains – and found significantly increased levels of the short form in the specimens from individuals with psychiatric disorders.

While many genes have been implicated in schizophrenia based on family studies, there has been little functional evidence for alteration in the proteins that are actually involved, but with CAPON there does, indeed, appear to be functional evidence.

“If CAPON really does disrupt this cellular pathway so the neurons cannot signal when and where they are supposed to, there is a point of entry for therapeutics,” Firestein said. “While we can’t make the therapeutics right now, we may have established some targets.”