Effective Brain Communication Impeded by “New” Genetic Mutations

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Michael O’Donovan, M.D., Ph.D. - Brain & behavior research foundation Lieber Prize Winner
Michael O’Donovan, M.D., Ph.D.

From The Quarterly, Spring 2014

One of the mysteries of schizophrenia and other neuropsychiatric illnesses with heritable genetic characteristics is that even though patients are less likely than healthy people to have children, the frequency of illness does not seem to decline. The incidence of schizophrenia, for example, is steady at about one percent of the population, over time and across human societies.

One important reason for this is that while schizophrenia has strong genetic roots, it is sometimes not an inherited genetic illness. Some unknown fraction of cases is caused by de novo gene mutations (new mutations that appear in a child but are not found in either parent). These mutations are the result of a normal error rate in the combining of genetic material that occurs whenever a sperm fertilizes an egg. The error rate is very small; all of us have such errors in our genome, but the key question is whether they can interrupt the work of key genes needed for normal functioning.

In a study led by 2012 Brain & Behavior Research Foundation Lieber Prizewinners, Drs. Michael O’Donovan and Michael Owen of Cardiff University in the United Kingdom, a multi-institutional team conducted the largest study to date examining the protein-coding portions of the genome in so-called “schizophrenia trios.” These family groups are comprised of a child diagnosed with schizophrenia and parents. The study sample included 623 trios where the DNA of parents allowed the researchers to identify mutations in the genome sequences of the affected children that were not present in either parent.

The researchers report, in a paper published in Nature on January 22, 2014, that they were able to identify de novo mutations in children with schizophrenia. This may help explain why schizophrenia persists in the human population at a constant level. Importantly, their findings also point to similar causative genetic malfunctions. In both of these new studies, mutations identified in patients with schizophrenia were disproportionately found in genes encoding proteins needed for proper cell-to-cell communication and for regulation of the plasticity* or strength of synapses that had been implicated in a previous study by Drs. Owen and O’Donovan.

Dr. Owen highlighted that “this degree of convergence from several studies is unprecedented in schizophrenia genetics and tells us that for the first time we have a handle on one of the core brain processes that is disrupted in the disorder.”

The findings also suggest that these mutations may be shared by other brain and behavior disorders. Dr. O’Donovan commented: “The fact we’ve been able to identify a degree of overlap between the underlying causes of schizophrenia and those in autism and intellectual disability suggests that these disorders might share some common mechanisms.”

TAKE AWAY: "De novo" genetic mutations––those changes in DNA sequence that are not directly inherited––are linked to altered synaptic processes in schizophrenia.

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