From The Quarterly, Spring 2014

A team led by scientists who have received funding from the Brain & Behavior Research Foundation has searched the protein-encoding portions of the human genome––the “exome”*—for rare variations (so called “point mutations” and small insertions and deletions) that can help explain what goes wrong in schizophrenia. Their work adds to a growing body of evidence indicating that the disease is not caused by one single gene or mutation, but by many different genetic anomalies that occur in a large number of combinations.

Identifying genetic regions, or better, pinpointing specific genes in which mutations confer higher risk for illness, is extremely valuable to developing better diagnostic tools and treatments. On January 22, 2014, a team that included Shaun M. Purcell, Ph.D., recipient of a 2006 NARSAD Young Investigator Grant, and Pamela Sklar, M.D., Ph.D., who has received three NARSAD Grants (Young Investigator in 1995 and 1998 and Independent Investigator in 2006), reported in Nature the results of a large study of the exome. These protein-encoding portions of our DNA, which comprise less than 2 percent of the full human genome, are thought to harbor a large majority of disease-causing mutations. This is because the protein output of such genes is so vital to all of our bodily processes and functions, including those of the brain.

Dr. Purcell, of the Broad Institute, Harvard University and the Icahn School of Medicine at Mount Sinai, and Dr. Sklar, also at Mount Sinai, with colleagues, scrutinized the protein-coding DNA of more than 5,000 people in a Swedish sample: 2,536 had schizophrenia and 2,543 were healthy controls. The team was able to identify several small sets of genes––about 50 genes altogether––in which rare mutations were significantly more common in patients with schizophrenia than in healthy people. “We found out that the rarest, most severe mutations—the most likely to damage a protein—contribute to schizophrenia risk,” explained Dr. Sklar.

“Despite the considerable sample sizes, no individual gene could be unambiguously implicated,” commented Dr. Purcell. “Taken as a group, however, genes involved in neural function and development showed greater rates of disruptive mutations in patients. This finding suggests that many genes underlie risk for schizophrenia and so any two patients are unlikely to share the same profile of risk genes.”

The team found that the genes identified encode proteins that work together at the synapse* to facilitate communication between neurons. It has long been suspected that schizophrenia might stem from problems at the synapse, but there has been no conclusive evidence. “Our work adds to prior work that has implicated disruption of synaptic processes in schizophrenia,” the team concluded. “Although we cannot yet use rare mutations to partition patients into more homogeneous clinical groups, this remains among our central goals.”

TAKE AWAY: New study identifies genetic changes in schizophrenia that manage the strength of connections and the communication between brain cells.