New studies show that many rare mutations contribute to schizophrenia risk

Researchers from the Broad Institute and several partnering institutions have taken a closer look at the human genome to learn more about the genetic underpinnings of schizophrenia. In two studies published this week in Nature, scientists analyzed the exomes, or protein-coding regions, of people with schizophrenia and their healthy counterparts, pinpointing the sites of mutations and identifying patterns that reveal clues about the biology underlying the disorder.

One study compared gene sequences from 2,500 people with schizophrenia to 2,500 healthy individuals from the same population. The second study looked for new mutations that might have occurred in protein coding genes by examining gene sequences from more than 600 schizophrenia trios (individuals with the disorder and their unaffected mothers and fathers). Both studies yielded further evidence that the disorder arises from the combined effects of many genes – a condition known as “polygenicity.” The studies also suggest that genetic alterations tended to cluster in a few networks of functionally-related genes.

Schizophrenia, a psychiatric disorder often characterized by hallucinations, paranoia, and a breakdown of thought processes, is known to be highly heritable. It affects roughly 1 percent of all adults, and individuals with immediate relatives who suffer from the disorder are at approximately ten times greater risk. While this high rate of heritability has long been recognized, previous genetic studies have struggled to identify specific genes that cause schizophrenia.

The two current studies, which are the largest of their kind to date, looked for mutations that were effectively invisible in previous studies: they detected changes at the scale of single nucleotides – substitutions, insertions, or deletions of individual bases or “letters” in the genetic code.

“Despite the considerable sample sizes, no individual gene could be unambiguously implicated in either study. Taken as a group, however, genes involved in neural function and development showed greater rates of disruptive mutations in patients,” explained Broad senior associate member Shaun Purcell, who played key roles in both studies. “That finding is sobering but also revealing: it suggests that many genes underlie risk for schizophrenia and so any two patients are unlikely to share the same profile of risk genes.”

Purcell, who is also a research scientist at Massachusetts General Hospital (MGH) and an associate professor of psychiatry at Mount Sinai’s Icahn School of Medicine, served as first author of one of the papers (Purcell et al.), which compared the exomes of individuals with schizophrenia with those from healthy individuals from the same population in Sweden. The researchers involved in the work hailed from nine institutions, including the Broad, Mount Sinai, and MGH.

The second paper (Fromer et al.) reported similar findings. That study, which was conducted by a multi-institutional collaboration that included the Broad Institute’s Stanley Center for Psychiatric Research, Mount Sinai, Cardiff University, the Wellcome Trust Sanger Institute, and six other research institutions, looked for de novo mutations – alterations in an offspring’s genome that do not exist in the genomes of the parents, and therefore cannot be attributed to heredity. Such mutations account for roughly 5 percent of schizophrenia cases.

Both studies found that mutations were distributed across many genes, and the research teams discovered similar patterns in the distribution of mutations across gene networks. Many of the genes that bore mutations shared common functions: they tended to be part of gene networks that govern synaptic function, including the voltage-gated calcium ion channel, which is involved in signaling between cells in the brain, and the cytoskeletal (ARC) protein complex, which plays a role in synaptic plasticity, a function essential to learning and memory.

“From a scientific standpoint, it’s reassuring to see different methods of studying the genetics of schizophrenia converge on the same sets of genes. These varied approaches are pointing toward the same underlying biology, which can be followed up in future research,” said Steven McCarroll, who was an author on both papers. McCarroll is director of genetics for the Broad’s Stanley Center for Psychiatric Research and a professor in genetics at Harvard Medical School.

The analysis of de novo mutations also revealed significant overlap between those found in schizophrenia and de novo mutations previously linked to autism and intellectual disability, a finding that may influence the approach researchers take in follow-up studies.

The authors argue that both papers demonstrate that genome sequencing will continue to be a powerful tool in the study of schizophrenia, though many more samples will need to be sequenced before the genetics of this complex disorder can be fully understood.

“Few facts have been firmly established about the molecular or cellular causes of schizophrenia, and that’s because many traditional scientific approaches can’t be used to study the disorder: you can’t grow it in a dish, and there aren’t very good animal models for it,” McCarroll explained. “We think that genomes are the path out of the darkness, and that these studies and others like them will ultimately provide the molecular clues we will need to map out the pathophysiology of the disorder.”

Stanley Center director Steven Hyman and Ed Scolnick, the Stanley Center’s chief scientist, thanked the institutions that collaborated on the studies.

“The genetic analysis of schizophrenia is yielding remarkably promising results because scientists around the world have worked collaboratively for years to recruit and study the large number of patients and comparison subjects needed to pick out rare genetic variants associated schizophrenia against the staggeringly complex background genetic variation that characterizes humanity. Phrases like ‘finding needles in haystacks’ do not begin to do justice to this shared global effort,” Hyman said.

Scolnick emphasized that this collaboration is accelerating research that will ultimately benefit patients.

"The exome sequencing data in these papers together with ongoing whole-genome association studies in patients with schizophrenia are helping to unravel the pathogenesis of this devastating illness,” Scolnick said. “This work is building a roadmap which will inexorably lead to better treatments for patients and families.”

Funding for these studies was provided by the National Institute of Mental Health, the National Human Genome Research Institute, the Stanley Medical Research Institute, the Sylvan Herman Foundation, Fidelity Foundations, a philanthropic gift from K. and E. Dauten, the Friedman Brain Institute and the Icahn Institute for Genomics and Multiscale Biology at Mount Sinai, the Karolinska Institutet, Karolinska University Hospital, Swedish Research Council, the Söderström Königska Foundation, the Netherlands Scientific Organization, the Medical Research Council (MRC), the European Community’s Seventh Framework Programme, the Wellcome Trust, and European Commission.

Researchers from the Broad Institute’s Stanley Center for Psychiatric Research and Medical and Population Genetics Program (MPG) contributed to Purcell et al., along with scientists from the Icahn School of Medicine at Mount Sinai; the Analytic and Translational Genetics Group at MGH; Karolinska Institutet in Stockholm, Sweden; KU Leuven, Belgium; The Wellcome Trust Sanger Institute; The University of Edinburgh; University of North Carolina, Chapel Hill; and Harvard Medical School.

Researchers affiliated with the Stanley Center and MPG at the Broad Institute were involved in Fromer et al., along with scientists from the Division of Psychiatric Genomics and the Friedman Brain Institute at Mount Sinai’s Icahn School of Medicine; the Institute of Psychological Medicine and Clinical Neurosciences at Cardiff University; Wellcome Trust Sanger Institute; University of Tartu, Estonia; Medical University - Sofia, Bulgaria; The University of Edinburgh, University of Helsinki, Finland; Harvard Medical School and MGH.

Papers cited:

Purcell et al. “A polygenic burden of rare disruptive mutations in schizophrenia.Nature DOI: 10.1038/nature12975

Fromer et al. “De novo mutations in schizophrenia implicate synaptic networks.Nature DOI: 10.1038/nature12929

About the Broad Institute of Harvard and MIT
The Eli and Edythe L. Broad Institute of Harvard and MIT was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.

Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to