Schizophrenia, a chronic, often debilitating mental illness, runs in families with a higher incidence among people who have a relative with the disorder.  Two new studies, published in the journal Nature, found that a very large number of rare genetic mutations contribute to a risk for the disease, rather than only a few "faulty" genes. “Now that we have this critical information, we can embark on the kind of massive-scale network analysis that our scientists have successfully used to characterize other complex diseases and start to think about new ways to treat these patients,” said Dr. Eric Schadt, director at the Institute for Genomics and Multiscale Biology at the Icahn School of Medicine at Mount Sinai Hospital.

Two Studies

Exons are short sequences of DNA that represent the regions in genes which are translated into protein, the verbs or action words within the vocabulary that is the human genome. About 180,000 exons exist in the human genome so they collectively constitute about one percent of the human genome, and the portrait of all of them together is known as an exome. Because researchers can more quickly and easily sequence an exome than a whole genome, exome sequencing functions as a cheaper but effective alternative. Ultimately, an exome sequence is to a genome sequence as juicing is to whole vegetables: easier to digest yet still extremely valuable.

In the first of the two studies, “A polygenic burden of rare disruptive mutations in schizophrenia,” researchers performed exome sequencing on 2,536 patients with schizophrenia as well as 2,543 unaffected individuals, which were then collected by the Karolinska Institute in Stockholm, Sweden. Dr. Shaun Purcell, head of the Center for Statistical Genomics at Mount Sinai, and his co-authors observed that many ultra-rare mutations across dozens of genes — particularly those related to proteins that influence brain circuitry — contribute to a person’s risk of schizophrenia.

In the second study,De novo mutations in schizophrenia implicate synaptic networks,” researchers led by Menachem Fromer performed exome sequencing on 623 trios (two parents and one affected child) from Bulgaria. After analysis of de novo mutations, the researchers found some overlap between genes implicated in schizophrenia with ones already associated with autism and intellectual disability.

Together, both studies gathered clinical and genetic information on more than 3,000 affected individuals, thus producing the world’s largest database on schizophrenia, a resource many believe will be invaluable to the biomedical community. “The sheer volume of data generated in these projects is remarkable and suggests new ways of thinking about the role of rare mutations in schizophrenia,” Purcell stated in a press release. “Although the complexity of the genetics is sobering, these types of studies should provide a firm base from which we can chart a course toward the ultimate goal of subtyping patients and offering a more personalized treatment path than the one-size-fits-all approach currently used.”

Schizophrenia Symptoms

Examples of people affected by schizophrenia have been recorded throughout history; it is not a new or newly diagnosed disability. Paranoia is a common symptom of the brain disorder, along with delusions, auditory and visual hallucinations, and psychosis. Schizophrenia is known to interfere with a person's abilities to think, manage emotions, make decisions, and relate to others. People with the disorder may believe others can read their minds or control their thoughts. They may even hear voices no one else hears. Sometimes people with schizophrenia seem perfectly fine until they discuss what it is they are really thinking.

The course of the illness is known to be unique for each person. Although it affects men and women with equal frequency, the symptoms of schizophrenia most often appear in men during their late teens or early twenties, while women often begin to express symptoms of the illness in their late twenties or early thirties. Schizophrenia occurs in one percent of the general population worldwide, while occuring in 10 percent of people who have a parent, brother, or sister with the disorder. Today, patients are treated with antipsychotic medications that have seen little innovation over the last 20 years.


Sources: Purcell S, Moran JL, Fromer M, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014.

Fromer M, Pocklington AJ, Kavanagh GH, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014.