Schizophrenia is one of the most prevalent, tragic, and frustrating of all human illnesses, affecting about 1% of the human population, or 2.4 million Americans . Decades of research have failed to provide a clear cause in most cases, but family clustering has suggested that inheritance must play some role. Over the last five years, multiple research projects known as genome-wide association studies (GWAS) have identified dozens of common variations in the human genome associated with increased risk of schizophrenia . However, the individual effects of these variants are weak, and it’s often not been clear which genes were actually affected by the variations. Now, advances in DNA sequencing technology have made it possible to move beyond these association studies to study the actual DNA sequence of the protein-coding region of the entire genome for thousands of individuals with schizophrenia. Reports just published have revealed a complex constellation of rare mutations that point to specific genes—at least in certain cases.
While there are drugs that can control the hallucinations, paranoia, and other symptoms of schizophrenia, we desperately need new treatments that are more effective and cause fewer side effects. That’s a tall order, because schizophrenia is a very tough disease to study. It’s not easy to replicate this complicated neurological disorder in a dish of cells or animal models. It’s also difficult to design and carry out studies to gauge the impact of possible environmental risk factors, such as exposure to viruses and prenatal nutrition.
Recognizing that increasingly sophisticated genetic studies might provide further clues, a couple of new NIH-funded studies [3,4] were carried out by a multidisciplinary team from the United States, United Kingdom, Sweden, Finland, Estonia, and Bulgaria, probing the DNA of large numbers of people with schizophrenia.
In the first study, researchers led by the Broad Institute of MIT and Harvard, Cambridge, MA, and the Icahn School of Medicine at Mount Sinai, New York, sequenced the protein-coding region of the genome, called the exome, in more than 2,500 Swedish people with schizophrenia and 2,500 without the disease. By closely examining the 30 million DNA letters in each participant’s exome, the researchers were able to detect tiny changes in the DNA code that were not detectable in prior GWAS projects. These changes included the deletion or substitution of a single letter of DNA, called “point mutations,” and insertions or deletions of a few extra DNA letters. While these changes might seem minor, they actually have the potential to affect the functions of the proteins encoded by genes in a major way.
Despite the large number of people studied, no one gene emerged as the major culprit in schizophrenia. But the analysis did show that individuals with schizophrenia had a higher rate of rare mutations than controls, and that these mutations tended to be concentrated in a few key gene networks involved in the central nervous system. Some of the mutations, such as those in the genes coding for voltage-gated calcium ion channel, the activity-regulated cytoskeleton-associated scaffold protein (ARC), and the N-methyl-D-aspartate (NMDA) receptor, have the potential to interfere with the ways in which neurons communicate with each other. Other mutations were found to be clustered in postsynaptic density genes, which are critical for learning, memory, and synaptic plasticity—the remodeling of neural connections and networks during development.
The second study took a different approach. Researchers scrutinized the exomes of 623 “trios” from Bulgaria, each of which consisted of a person with schizophrenia along with his or her non-schizophrenic parents. The aim was to search for exome mutations in the individuals with schizophrenia but that were not present in either of their parents. This could only happen if these mutations were spontaneous, or de novo, rather than inherited. (It is estimated that all of us have one or two de novo exome mutations that are not present in our parents.)
As expected, this analysis uncovered de novo mutations in schizophrenia exomes—as would be true for any group of individuals. But importantly, the mutations did not appear in a random pattern; instead, there was a higher frequency of mutations in many of the same genes implicated in the first study. This adds confidence to the results, because although the teams took two different approaches, they still zeroed in on the same underlying biology—valuable information for those working on better ways to diagnose, treat, and possibly even prevent schizophrenia.
Another interesting finding from the second study was the identification of de novo genetic mutations that overlapped with de novo mutations uncovered in previous studies of autism spectrum disorder and intellectual disability. This suggests that several genes may play a role in all three conditions, indicating they may have more in common than once thought.
We still have a long way to go to identify all of the causative genetic and environmental factors for schizophrenia and ultimately to use that information to design new approaches to prevention and treatment. But these two studies get us an important step further along that path.
 The Numbers Count: Mental Disorders in America. (National Institute of Mental Health/NIH)
 Catalog of Published Genome-Wide Association Studies. (National Human Genome Research Institute/NIH)
 A polygenic burden of rare disruptive mutations in schizophrenia. Purcell SM et al. Nature. 2014 Jan 22. [Epub ahead of print]
 De novo mutations in schizophrenia implicate synaptic networks. Fromer M. et al. Nature. 2014 Jan 22. [Epub ahead of print]
Schizophrenia. (National Institute of Mental Health/NIH)
NIH Support: National Institute of Mental Health; National Human Genome Research Institute