No Single Gene Is Responsible for Schizophrenia

Many TV shows, novels, biographies, and movies in recent years have been released that speculate why it is that some families develop schizophrenia more often than others. Six Schizophrenic Brothers is one of the more recent films, while biographies like A Beautiful Mind still ground the canon as a classic in the public’s references to schizophrenia.

This cultural knowledge is mostly expressed by what we do currently know, which has been gathered by scientific studies and surveys. However, what we know about schizophrenia is small and repetitive and includes some of these items:

• Schizophrenia occurs globally–in all cultures and throughout time.
• Schizophrenia is ranked twentieth out of all medical disorders in mortality rates.
• Lifespan can be reduced by 12-15 years.
• Family history of psychosis appears pronounced, especially in families where mental health diagnoses appear in clusters of relatives.
• Risk for developing schizophrenia is more associated with the fact that families have mental illness at all, rather than having been specifically diagnosed with schizophrenia.
• In twins, heritability is 60-65 percent.

There has been a race to search for biological indications that this disorder is a physical one, not just a social and cultural one. But it doesn’t seem that heritability is that straightforward. Scientists have been working on studies for years now that isolate potential genetic variants that could be responsible for the development of schizophrenia.

A new review published this month in Nature reveals what we currently know as a scientific field about schizophrenia. What its authors call the “genomic architecture” seems to be made up of not one, but multiple sets of genes. And those genes are still unknown.

Several large famous studies in the field like the genomic-wide association study (GWAS), whole-genome sequencing study (SETD1A), and copy number variants (CNVs) use gene mapping and other technologies to first observe and assess whether or not there are common alleles (genes) that are associated with the disorder. Some of these studies, established 10 years ago in 2014, have withstood the test of time and have produced results indicating that some genes occur more than others in the disorder, and have been replicated (a vital criterion for establishing a true scientific discovery). But that doesn’t mean we know which genes actually cause schizophrenia, if there are any at all.

Three recent meta-analytic studies have taken known studies and used various methods to determine the frequency of genetic variants that co-occur with the diagnosis of schizophrenia. They looked for causally determinate genes, including rare variants that have more weight in affecting a person with the disorder to common variants with weaker links to the diagnosis.

According to the researchers in the Nature review, the only conclusion that can be drawn from the history of research on schizophrenia’s genetics is that there is simply no one set of genes that determine whether a person will develop schizophrenia. No single causal variant of genes has been found to claim culprit for the genetic makeup of schizophrenia.

There have been variants that have been found to be more common in those with the diagnosis more than others, including genes that that appear in 0.3 percent of people with schizophrenia compared to 0.0049 percent of health controls, which are one of the only numbers that even have a tenth decimal in the assessments. If that number seems small, that’s because it is, and why researchers hesitate to claim any one gene for being responsible for the expression of the disorder.

So What Do We Know?

Through the multi-analyses of the existing literature on the biological components of schizophrenia, researchers have extracted several main takeaways.

It appears that schizophrenia is a disorder that actually is the result of multiple clusters of genetic variants, or what is referred to as a polygenic disorder, meaning there is no single gene that is responsible for the expression of psychotic symptoms, even though it appears that way as society witnesses documentaries like Six Schizophrenic Brothers.

What do we do next? The authors express the researchers’ limitations. We are limited by our current technologies. The scientific community does not have, at this time, a way to model polygenic human variation. The authors are calling for more donors of brains, more brain datasets, and tools especially from other regions of the world and not just Europe.

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The implications of this review reveal the need to innovate the ways we study schizophrenia and mental illness at large. Though researchers wanted to believe that they could find a single gene that was responsible for the development of schizophrenia, now they know better.