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What causes schizophrenia?

This common question is typically answered by noting that a variety of genetic and environmental factors can raise or lower a person’s risk for developing this type of mental illness. In the case of genetic influences, the discussion is often limited to observations that schizophrenia seems to be more common among people who are closely related to each other.

For example, as the UK’s National Health Service has reported, researchers who study mental illness among twins have long realized that there is an association between genetics and schizophrenia:

  • If one identical twin has schizophrenia, there is a one in two (50%) chance that the other twin will also develop this disorder – even if the identical twins were raised in different environments.
  • Among non-identical twins, the likelihood that the second twin will develop schizophrenia if the first twin has the disorder falls to about one in eight (12.5%).

Even though the prevalence of schizophrenia among non-identical twins described above may appear to be relatively low, it is orders of magnitude larger than among the general public. According to the World Health Organization (WHO), the global rate of schizophrenia is about one in 300 people (or about 0.32% of the world’s population).

Noting that schizophrenia is more common in people who have a family history of the disorder was an important step in establishing a genetic connection to this disorder. This connection came into sharper focus earlier this year, thanks to a multinational study that involved an analysis of DNA samples from more than 320,000 people.

The Genetics of Schizophrenia

On April 8, 2022, the journal Nature published a study that appears to have uncovered the clearest evidence yet of the many potential genetic causes of schizophrenia. This study, which was conducted under the auspices of the Psychiatric Genomics Consortium, was led by researchers from Cardiff University in Wales.

Highlights of this study included the following:

  • Researchers analyzed DNA samples from 320,404 people (including 76,755 who had schizophrenia and 243,649 who did not have the disorder).
  • The researchers found evidence of genetic links to schizophrenia in 287 regions of the human genomes they studied.
  • The research team used what they described as “advanced methods” to identify 120 specific genes that seem to influence a person’s risk for developing schizophrenia.
  • The genetic links to schizophrenia were confined to neurons, which transmit information throughout the central nervous system. No other types of cells or tissues appeared to have a genetic association with schizophrenia.

In an April 6 article that announced the study’s results, co-lead author Michael O’Donovan of Cardiff University’s Division of Psychological Medicine and Clinical Neurosciences noted that the specificity of his team’s research may lead to advances in treatment for schizophrenia.

“Previous research has shown associations between schizophrenia and many anonymous DNA sequences, but rarely has it been possible to link the findings to specific genes,” O’Donovan said.

“The present study not only vastly increased the number of those associations, but we have now been able to link many of them to specific genes,” O’Donovan added, “[which is] a necessary step in what remains a difficult journey towards understanding the causes of this disorder and identifying new treatments.”

SCHEMA Study Identifies 10 Genes Related to Schizophrenia

The April 8, 2022, issue of the journal Nature that included the Psychiatric Genomics Consortium study also featured research from the Schizophrenia Exome Meta-Analysis (SCHEMA) group. The SCHEMA study investigated variations in 10 genes that appear to be linked to an elevated risk of developing schizophrenia.

According to a December 1, 2022, article on the website of the Brain & Behavior Research Foundation, people who have the genetic variations identified by the SCHEMA study may have as much as a 50% chance of developing schizophrenia. This is similar to the risk experienced by identical twins of people who have schizophrenia.

Features of the SCHEMA study included the following:

  • This study involved an analysis of genetic samples from 121,248 people, including 24,248 who had schizophrenia.
  • The researchers examined the exomes of these samples. The exome is the small section of the full genome that is involved with encoding proteins.
  • Mutations in the 10 identified genes can lead to both diminished protein production and impaired functioning of the proteins that are produced.

“One theory of schizophrenia pathology is that synaptic communication is disrupted, perhaps in neurons sensitive to excitatory glutamate signals,” wrote Tarjinder Singh, PhD, who participated in the SCHEMA study. “The SCHEMA discovery of rare mutations in GRIN2A and in another gene called GRIA3 are solid genetic evidence of this mechanism in schizophrenia causation and/or dysfunction.”

Genes, Schizophrenia, & Brain Structure

As Michael O’Donovan noted in the article about his team’s research, the recent studies by the Psychiatric Genomics Consortium and the SCHEMA team were not the first efforts to explore the genetic underpinnings of schizophrenia.

In June 2021, the journal JAMA Psychiatry published a study titled “Genetic Association Between Schizophrenia and Cortical Brain Surface Area and Thickness.” This study, which involved a review of genetic samples from 139,053 participants, was led by Weiqiu Cheng, PhD, of the Oslo (Norway) University Hospital & Institute of Clinical Medicine.

In the introduction to their study, Dr. Cheng’s team noted the following:

  • Prior research indicates that the genetic risk of schizophrenia can affect early brain development and has been associated with several structural abnormalities in the brain.
  • MRIs have found that people with schizophrenia have smaller cortical surface area and thinner average cortical thickness than do people who don’t have this disorder.
  • These findings suggest that genetic mechanisms that increase a person’s risk for developing schizophrenia may also influence their brain anatomy.

After conducting a statistical analysis of the 139,053 genetic samples that were included in this study, Dr. Cheng’s team reached the following conclusions:

  • There is a shared genetic basis (including common locations on the human genome) among schizophrenia, cortical surface area size, and average cortical thickness.
  • There is a clear genetic overlap between cortical structure and schizophrenia.
  • Certain immune functions and processes may be linked with both cortical development and schizophrenia.

“In this genetic association study, data sets revealed that 94% of the genetic variants associated with total cortical surface area and all variants associated with average cortical thickness were also associated with the genetic risk of schizophrenia, despite nonsignificant genetic correlations,” Dr. Cheng’s team reported.