January 22, 2014. Rare genetic changes found in the DNA of people with schizophrenia point to problems with how brain cells communicate, according to two new studies published January 22 in Nature. An international crew of researchers joined forces to comb through the protein-encoding parts of the genome (the “exome”) to find suspicious, single-letter changes, called point mutations, in the DNA.
Exome sequencing thousands of people, the studies provide the largest to date scans of the exome in schizophrenia. The researchers detected rare point mutations in many different genes, bolstering the idea that risk for schizophrenia stems from problems with different types of proteins rather than from a single culprit.
“We found out that the rarest, most severe point mutations—the most likely to damage a protein—contribute to schizophrenia risk,” said Pamela Sklar at Mount Sinai School of Medicine in New York City, who was an author on both studies.
Sklar co-led one study with Shaun Purcell of The Broad Institute of Harvard and MIT in Cambridge, Massachusetts, which looked for rare mutations occurring more frequently in 2,536 people with schizophrenia than in 2,543 control subjects. The second study, led by Michael O’Donovan and Michael Owen of Cardiff University, United Kingdom, scanned the exomes of 617 people with schizophrenia and both parents to find mutations that spontaneously arose in sperm or egg cells prior to conception. These “new” mutations—carried by the person with schizophrenia but not by either parent—are more likely to be damaging.
Although point mutations in schizophrenia hit many different genes, the genes encode proteins that work together at the synapse, a specialized conduit for communication between neurons. It has long been suspected that schizophrenia might stem from problems at the synapse, though conclusive evidence has not been found. In the two new studies, genes encoding a complex of proteins important at the receiving side of the synapse were hit more often by rare variants in schizophrenia than they were in controls. Just as problems with any part of an engine can halt a car, the findings suggest that breaking one of many different parts of the synapse could hamper neuron communication, which could produce the disordered thinking and other symptoms of schizophrenia. (For more details, see the related news story.)—Michele Solis.