Mutations behind risk of developing schizophrenia identified

Researchers have said that the overall number and nature of mutations - rather than the presence of any single mutation - influences an individual's risk of developing schizophrenia, as well as its severity.

Maria Karayiorgou, MD, professor of psychiatry and Joseph Gogos, MD, PhD, professor of physiology and cellular biophysics and of neuroscience, and their team sequenced the "exome"-the region of the human genome that codes for proteins-of 231 schizophrenia patients and their unaffected parents.

The researchers compared sequencing data to look for genetic differences and identify new loss-of-function mutations-which are rarer, but have a more severe effect on ordinary gene function-in cases of schizophrenia that had not been inherited from the patients' parents. They found an excess of such mutations in a variety of genes across different chromosomes.

Using the same sequencing data, the researchers also looked at what types of mutations are commonly passed on to schizophrenia patients from their parents. It turns out that many of these are "loss-of-function" types. These mutations were also found to occur more frequently in genes with a low tolerance for genetic variation.

The researchers then looked more deeply into the sequencing data to try to determine the biological functions of the disrupted genes involved in schizophrenia. They were able to verify two key damaging mutations in a gene called SETD1A, suggesting that this gene contributes significantly to the disease.

SETD1A is involved in a process called chromatin modification. Chromatin is the molecular apparatus that packages DNA into a smaller volume so it can fit into the cell and physically regulates how genes are expressed. Chromatin modification is therefore a crucial cellular activity.

The finding fits with accumulating evidence that damage to chromatin regulatory genes is a common feature of various psychiatric and neurodevelopmental disorders. By combining the mutational data from this and related studies on schizophrenia, the authors found that "chromatin regulation" was the most common description for genes that had damaging mutations.

The findings have been published in the journal Neuron.