Developing Risk Profiles for Schizophrenia

Developing Risk Profiles for Schizophrenia

Posted: November 22, 2014

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From The Quarterly, Fall 2014

Results of the largest study ever undertaken to understand the genetics of schizophrenia appeared in the prestigious journal Nature on July 24th. Thomas Insel, M.D., Director of the National Institute of Mental Health, said that “a giant step forward” had been taken toward a better understanding of the genetics of schizophrenia, which could ultimately lead to better identification of those at risk of developing the illness, and to the development of new treatments.

Hundreds of scientists participating in the international Psychiatric Genomics Consortium (PGC) contributed to the mammoth study, which analyzed blood samples contributed by 36,989 people with schizophrenia and 113,075 healthy controls of diverse races and ethnicities. The bottom line: variations relative to the norm in 108 different genetic “loci” (locations containing genes along the full length of the human genome) were associated in this sample with the occurrence of schizophrenia. The loci were among genes expressed in the brain and in neurons—about three-fourths of the variations detected in the study are active mainly or exclusively in cells of the brain.

One of the key team members was Patrick Sullivan, M.D., of the University of North Carolina, recipient of a 2010 NARSAD Distinguished Investigator Grant and winner of this year’s Lieber Prize for Outstanding Achievement in Schizophrenia Research. Dr. Sullivan organized the psychiatric genetics community into the PGC in 2007, and it now consists of more than 500 investigators across 80 institutions in 25 countries. One of the team leaders was Michael O’Donovan, M.D., Ph.D., of Cardiff University, United Kingdom, the 2012 Lieber Prizewinner. First author on the paper is this year’s recipient of the Sidney R. Baer, Jr. Prize for Innovative and Promising Schizophrenia Research, Stephan Ripke, M.D., of the Broad Institute.

Only 25 of the 108 genome locations had previously been associated with schizophrenia; 83 were new and will lead to much follow-up. Some of the 25 locations previously noted suggest defects in genes that have been consistently associated with higher risk for schizophrenia. One such gene, DRD2, tells cells in the brain how to encode a protein that serves as a receptor (docking port) for the neurotransmitter dopamine.* Those receptors are the targets of all known antipsychotic medications, the first of which was discovered some 60 years ago.

Other genes previously linked with the illness and pinpointed in the new study include those involved in transmission of glutamate—the brain’s key “excitatory” neurotransmitter—and in synaptic plasticity, the process in which communication nodes between neurons in the brain gain and lose strength in response to different stimuli and conditions.

Possibly the most intriguing result was an association with genes related to the generation of the body’s innate immune system. This will fuel efforts, which have been increasing, to study the possible role of immunity in schizophrenia causation and what might be done to prevent it.