Rare embryo mutations may increase risk of developing schizophrenia

Rare genetic mutations that occur during the first few days of embryo development may increase the risk of developing schizophrenia in later life. The findings could help reveal new treatments.

Around 1 in 300 people have schizophrenia, with symptoms including hallucinations, muddled speech and a loss of interest in everyday activities. It is widely accepted that genetic factors play the largest role in whether someone develops the condition, with environmental factors such as low birth weight or the use of psychoactive drugs only having a minor influence. Despite this, researchers have only pinned down around a dozen of the genetic variants involved.

Now, Christopher Walsh at Boston Children’s Hospital in Massachusetts and his colleagues have found evidence that non-inherited, or somatic, mutations – those that occur by chance during embryo development – may contribute to schizophrenia risk later in life. All previous mutations linked to the condition are ones passed down from the parents.

The researchers analysed genetic data previously extracted from blood samples from more than 12,800 adults with schizophrenia and over 11,600 people without the condition.

They found that part of a gene called NRXN1 had been deleted in six people with schizophrenia, but not in people without the condition. As the mutation was present in between 14 and 43 per cent of blood cells in these six individuals, it must have occurred in a cell during the first few days of embryo development before propagating through descendants of that cell, says Walsh. In contrast, inherited mutations are generally present in every cell of the body.

“Based on previous work, we know mutations like this that are detected in the blood probably affect a similar proportion of other cell types in the body, including the brain, where schizophrenia takes hold,” says Walsh. NRXN1 is important for learning because it encodes for a protein that regulates the number and density of connections between nerve cells, or neurons, in the brain, he says.

In a different set of six participants with schizophrenia who had not responded to a schizophrenia drug called clozapine, the team found mutations in a gene called ABCB11 in between 18 and 27 per cent of their blood cells. This gene encodes for a protein involved in transporting digestive salts in the liver, but it hasn’t been previously linked to schizophrenia and its role in the brain is unclear, says Walsh. A small number of people without schizophrenia had these mutations, but it is possible they may develop the condition in the future, he says.

By analysing genetic data previously collected from people’s brains, the team found that ABCB11 was active in neurons that produce the “happy” hormone dopamine, and these cells are targeted by “almost all of our known drugs for schizophrenia”, says Walsh.

This suggests that having the ABCB11 gene may be required to get these drugs into the dopamine-producing neurons, and mutations disrupt this, says Walsh. “Targeting ABCB11 could be important for helping some of those drug-resistant patients become more treatable with the present drugs we do have.” But this needs to be tested, he says.

One limitation of the study is that the team lacks detailed information on lifestyle factors – such as people’s use of psychoactive drugs – that might differ between those with and without schizophrenia and thus affect the results, says Atsushi Takata at the RIKEN Centre for Brain Science in Japan.

Nevertheless, the findings “could provide novel insights into the biological process and mechanisms associated with this condition, which, in turn, may inform treatment development”, says Elliott Rees at Cardiff University, UK.