Schizophrenia: Gene discovery indicates risk and cause

Our understanding of schizophrenia has been stuck in a kind of black box for decades — experts say we don't really know what is going on inside the brain.

We know that schizophrenia is a serious mental condition, characterized by hallucinations, periods of psychosis and a detachment from reality.

The World Health Organization (WHO) estimates that schizophrenia affects about 1 in 300 people worldwide.

Only we don't really know why: Why it happens or how we can treat it.

"Our knowledge about schizophrenia is close to zero," says Stephan Ripke, a researcher at Berlin's Charitie university hospital and a co-author on one of two papers published in the science journal Nature on Wednesday (April 6, 2022).

Ripke and others in an international team say they have made a landmark discovery in the biological understanding of schizophrenia.

They say they have discovered at least ten gene mutations that strongly influence a person's likelihood of developing the disease and 120 more that could play a role.

Discovery may lead to new treatment

The researchers say they have a better understanding now of why schizophrenia happens biologically. Previously, researchers had focused on so-called environmental factors, such as a person's diet or whether they consumed recreational drugs.

Ripke says the discovery of the gene mutations will not make it easier to diagnose patients with schizophrenia earlier in life. But it could help scientists to estimate a person's risk and improve treatments for the illness with medicine.

There are medicines for schizophrenia but they do not address the disorder's root cause. The drugs we use today only tone down the effects of schizophrenia. But now that researchers know more about what's happening in the brain to cause schizophrenia, they may be able to develop better drugs to treat it.

First of two genetic studies

There are two new papers published in Nature. And both look at the genetics of schizophrenia from different angles.

One of the studies was conducted by the Psychiatric Genomics Consortium (PGC). That is led by scientists at the UK's Cardiff University.

They took a very broad approach by investigating the entire genome —  all of the genetic material in an organism — to search for a specific genetic variation that increases a person's risk of developing schizophrenia.

Analyzing DNA from some 77,000 people with schizophrenia and around 244,000 people without it, they discovered nearly 300 parts of the genome with genetic links to schizophrenia risk. Within those regions, they discovered 120 genes that could play a role in causing the disorder.

They found that risk for schizophrenia is only present in the brain and in genes concentrated in neurons — brain cells that help transmit messages from the external world to the brain and vice versa, allowing people to move and speak.

That process is facilitated by synapses, which connect neurons with other cells in the brain and body.

The second study

The other study took a narrower approach, but the results also point towards neurons and synapses as playing key role in a person's risk of developing schizophrenia.

It was conducted by the SCHEMA team, a joint effort led by the Broad Institute of MIT and Harvard. The researchers discovered ten genes with rare mutations that appeared to increase a person's schizophrenia risk and 22 more that could play a role.

"In general, any given person has a roughly one percent chance of developing schizophrenia in their lifetime," said Benjamin Neale, a SCHEMA co-author and member of PGC, in a press release. "But if you have one of these mutations, it becomes a 10, 20, even 50% chance."

Some of these genes pointed to problems at the synapse as a potential cause for the disease. Broad Institute scientists first discovered that in a 2016 study.

That paper marked the first time that the origins of schizophrenia had been linked to specific gene variants and helped explain why schizophrenia starts to develop in adolescence and early adulthood.

Instead of studying the entire genome, which offers a broader but less specific view, the SCHEMA researchers studied a small part of the genome called the "exome." The exome encodes proteins. Using exomes from around 24,000 people with schizophrenia and about 97,000 without it, they looked for variants that inhibited a gene's ability to create functioning proteins.

Two of the ten gene mutations discovered by the SCHEMA team were related to dysfunction at the synapse, which researchers had expected.

But the researchers say that the other eight genes have never before been associated with a brain disorder or neuron-specific function. That implies that there is a lot more work to be done.

What we still don't know

Schizophrenia usually starts presenting in patients in late adolescence and their 20s.

Researchers have been able to study the environmental aspect of the disease — they've found that where a person grows up, teenage cannabis use and nutrition during pregnancy can all play a role in its development.

Although scientists know that schizophrenia is 60 to 80% hereditary, they have little understanding of the genetics of the disease.

As Ripke said earlier, their knowledge about the biology of schizophrenia is "close to zero."

That's due to a number of problems that are not limited to schizophrenia, says Ripke. Those problems exist in many other mental illnesses — bipolar disorder or borderline personality disorder, for example.

First, there's no way to study the disease in animals, Ripke says. And it can't be diagnosed through a blood test or even a brain scan.

"We only have questions, answers and observations, and even the observations are not enough if we don't [share a] language. Basically, we need to know if the people have hallucinations, if they hear voices," says Ripke.

So, that rules out non-human animals because they can't talk to us and we can't talk to them. The importance of language in the diagnosis and subsequent study of schizophrenia means that research has to be done on humans. Ethical concerns have kept scientists from collecting the samples they need to facilitate genetic analysis once they do make that language-based diagnosis.

"We cannot take samples out of the living organ," says Ripke. "We cannot just take brain cells from schizophrenia patients."

Towards new schizophrenia medication

Today's schizophrenia medication is still based on a discovery made in the 1950s, says Ripke.

The first antipsychotic medication was chlorpromazine, which is still prescribed for the condition. Chlorpromazine blocks a person's dopamine receptors. There are other antipsychotic medications, but they all work in a similar way to chlorpromazine.

Chlorpromazine was originally developed as an anesthetic. Its use in psychiatry came about by accident when doctors found that the drug helped prevent hallucinations in psychiatric patients.

"It was not that somebody actually found a broken dopamine receptor or measured high levels of dopamine in the blood or in the brain or something like that," says Ripke. "That was not the case. It was just an incidental finding. It never came from research."

But the scientists say they have there's a better chance now of developing medication that addresses the root of the problem, rather than only the symptoms, like hallucination.

These enormous, population-wide DNA sequencing experiments are scientists' best bet at figuring out how to do that. But Ripke says that's only possible when people volunteer.

"The study would have never worked without the trust of thousands and thousands of patients who gave us their genetic information," says Ripke. "We are so utterly thankful to all the people who trusted us with their data."