Schizophrenia Linked to Mutations in Genes Critical to Synaptic Function

By Will Boggs MD

February 06, 2020

NEW YORK (Reuters Health) - People with schizophrenia have damaging mutations in genes that are critical to synaptic function, and these mutations are unique to each individual, according to a study in the Xhosa population of South Africa.

"Each person with schizophrenia in the study had different mutations, and most of the rare damaging mutations occurred in different genes," Dr. Jon M. McClellan of the University of Washington, in Seattle, told Reuters Health by email. "This suggests that most people with the illness have a different genetic cause. This helps explain why there is so much clinical heterogeneity in how the illness presents, and why there is so much variability in how affected persons respond to different medication treatments."

"We also were able to show that the risk of having schizophrenia increased for each additional private damaging mutation a person carried," he added. "While this has long been suspected, this was the first study to demonstrate that relationship."

Dr. McClellan and colleagues sought to identify and characterize genetic influences in schizophrenia in the South African Xhosa, not because they have an unusual prevalence of schizophrenia, but because African populations harbor the greatest wealth of human genetic diversity.

The researchers used whole-exome sequencing in 909 individuals with schizophrenia (cases) and 917 controls without schizophrenia.

Cases were significantly more likely than controls to harbor private damaging mutations in genes that were intolerant to such mutations, whereas there were no significant differences between cases and controls in benign mutations in mutation-intolerant genes.

Cases were also significantly more likely than controls to carry private damaging mutations in genes highly expressed in the brain and in genes that are involved in synaptic functioning, the researchers report in Science.

Cases were significantly more likely than controls to carry private damaging mutations in genes that have been shown to be downregulated in schizophrenia or autism or upregulated in bipolar disorder in brain tissue from other populations.

Applying the same methods to a case-control study of schizophrenia in the Swedish population yielded similar results, although results from the Xhosa yielded generally larger effect sizes, the researchers found.

"The concordance of analyses of the Xhosa and Swedish populations is important, because many findings in genetic studies of schizophrenia do not replicate across populations," they note.

"The findings fit an evolutionary model of schizophrenia," Dr. McClellan said. "Schizophrenia often occurs in individuals with no immediate family history of the illness, and affected persons tend to have fewer children. These observations suggest that new or recent damaging mutations are responsible for the illness. New mutations can cause an illness not found in close relatives, and mutations that negatively impact a person's ability to have children do not persist over generations."

"The more that we understand genetic causes of schizophrenia, the more likely we are to discover new more effective treatments," Dr. McClellan said.

Dr. Jasmina Mallet of University Hospital Louis Mourier, Paris Diderot University, in Paris, who studies the genetics of schizophrenia, told Reuters Health by email, "Africa could be the most informative continent for understanding the human genome and thus contribute to the understanding of genetics of schizophrenia. Until now, the majority of genetic studies were led in northern Europe."

"Interventions designed to remediate disruptions in synaptic structural organization and intracellular signaling pathways potentially could offer more specific therapeutic benefits than actual strategies (antagonists and/or agonists targeting at neurotransmitter receptors)," she said. "Current strategies hardly tackle cognitive and negative symptoms; we need new pharmacological approaches."

"The search for mutations in patients is not done enough in current practice," Dr. Mallet said. SOURCE: https://bit.ly/2GY2xGN Science, online January 31, 2020.

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