Mental health

Schizophrenic gene discovery

“Scientists say they have ‘fundamentally transformed’ the understanding of the genetics of schizophrenia,” BBC News has reported.

The news is based on a study looking at “sporadic schizophrenia” cases in people with no family history of it. Although the condition schizophrenia is already known to have a strong genetic component, new research has found that a large proportion of affected people with sporadic schizophrenia carry genetic mutations despite having no family history of the condition. Researchers identified 40 mutations affecting 40 different genes in individuals with sporadic schizophrenia, most of which were predicted to affect the structure and function of proteins produced by the body.

The results of this study suggest that schizophrenia has a genetic component even in individuals who don’t have a relative with it. This is as a result of new mutations that either arise in the individual sperm and egg cells or which occur very soon after the sperm fertilises the egg. The results emphasise the fact that schizophrenia is a very complex disease. However, future studies will be required to determine whether the mutations identified actually have a role in the disease, and to confirm the findings in larger numbers of individuals.

Where did the story come from?

The study was carried out by researchers from Columbia University, the HudsonAlpha Institute for Biotechnology, USA and the University of Pretoria, South Africa. It was funded by US National Institute of Mental Health, the Lieber Centre for Schizophrenia Research and the US National Alliance for Research on Schizophrenia and Depression.

The study was published in the peer-reviewed scientific journal Nature Genetics.

The story was well-reported by the BBC.

What kind of research was this?

This was a case-control genetics study that aimed to identify mutations in individuals with schizophrenia who did not have a family history of it – called “sporadic” cases. Although a person’s genetic make-up is thought to have a strong influence on whether they develop schizophrenia, sporadic cases account for a large proportion of people with the disease. The researchers wanted to assess whether sporadic cases of schizophrenia carried mutations that their parents did not carry. This type of mutation arises in the sperm or egg cells before fertilisation or very soon afterwards and therefore affects the offspring only, and not the parent.

This is the most appropriate type of study design to answer this question.

What did the research involve?

Fifty-three individuals with schizophrenia and their unaffected parents were recruited to form the sporadic (non-inherited) “cases” group. These cases did not have close relatives with schizophrenia or a related condition called schizoaffective disorder. Twenty-two unrelated healthy individuals and their parents formed the control group. Their close relatives did not have any reported mental illnesses either. All the people recruited for this study were from the Afrikaner population of European descent in South Africa, which meant that they shared a common genetic background.

Blood samples were taken from all 225 individuals recruited for this study. DNA was extracted from these samples, and the pieces of DNA which carried instructions for making proteins (collectively called the “exome”) were sequenced. The sequences from the cases and controls were compared to those of their parents to identify variations that were present only in the offspring. The predicted effect of the identified variations was then investigated using programmes modelling the effect of these changes on protein structure and function.

What were the basic results?

Twenty-seven out of 53 cases (about 51%) and seven out of 22 controls (about 32%) had at least one new mutation compared to their parents. This difference was not statistically different. The overall new mutation rate in these groups was similar to several estimates from other studies.

However, more of the new mutations seen in the cases were predicted to affect the sequence of proteins produced by the body. In the cases group, researchers observed 34 mutations that affected either one or two of the “letters” (nucleotides) that make up a DNA sequence. In addition to these one- and two-letter mutations (called “point mutations”) the researchers found four mutations that were additions or deletions of small numbers of nucleotides.

Thirty-two of the 34 point mutations identified were predicted to affect the sequence of the protein that would normally be produced, and 19 of these changes were predicted to be damaging to the function of the protein. The insertions and deletions identified either resulted in a shortened protein or deletion of a single of the “building blocks” of the protein (called amino acids). Other mutations were predicted to affect the protein-production process. None of these mutations were present in the controls. In contrast, only four of the seven mutations that were identified in the control subjects were predicted to affect the protein sequence.

All of the mutations identified occurred in different genes, and only one of the affected genes had been associated with schizophrenia in previous studies. Using several modelling programs, the researchers identified a number of mutations which they suggest as being more likely to have a role in the disease. One of these was mutations in a gene called DGCR2; the function of the protein encoded by this gene is unknown.

How did the researchers interpret the results?

The researchers concluded that new “protein-altering mutations contribute substantially to the genetic component of schizophrenia”, and that these “mutations account for more than half of the sporadic cases.” The researchers also suggest that the fact that schizophrenia and other psychiatric disorders are so complex means that mutations in many different genes could potentially contribute to causing these diseases.


The results of this study suggest that there may be a genetic component to schizophrenia, even among individuals who do not have a relative with it. The new mutations in these individuals either arise in the sperm and egg cells or very soon after fertilisation.

By analysing individuals with schizophrenia and healthy individuals and comparing their DNA with that of their parents, the researchers found that the overall new mutation rate was similar between the two groups and close to previously calculated estimates. However, the location and nature of these mutations in individuals with schizophrenia mean they were more likely to affect the body’s production of proteins than the types of mutations seen in the healthy controls.

Mutations in 40 different genes were identified in the 53 individuals with schizophrenia. Further studies will be required to determine whether the mutations actually have a role in the disease, and to confirm the results in larger numbers of people with schizophrenia.

The results emphasise the fact that schizophrenia is a very complex disease, and that there is more to be learned about the genetics of the condition.

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