Many rare mutations contribute to schizophrenia risk

Two new studies provide further evidence that schizophrenia arises from the combined effects of many genes. Dr. Patrick Sullivan of UNC is a co-author of one of the studies.

Many rare mutations contribute to schizophrenia risk
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Patrick Sullivan, MD

Media contact: Tom Hughes, (919) 966-6047,

Wednesday, January 22, 2014

CHAPEL HILL, N.C. – Two new studies published this week in Nature yielded further evidence that schizophrenia 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.

Dr. Patrick Sullivan, distinguished professor of genetics and psychiatry at the University of North Carolina School of Medicine and director of the Center for Psychiatric Genomics, is a co-author of one of the studies, which compared the gene sequences from 2,500 people in Sweden with schizophrenia to 2,500 healthy individuals from the same population.

“This landmark study shines bright light on a part of the genome we’ve never been able to see before,” said Sullivan. “It looks like schizophrenia is less a disease of changes in the structure of proteins, and more a problem of the amounts of proteins.”

This landmark study shines a bright light on a part of the genome we've never been able to see before.

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 Shaun Purcell, PhD, of the Broad Institute of MIT and Harvard, 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.”

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.

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.

“This study was an incredible amount of work by a big team over a decade,” said Sullivan. “If the final results were a single pixel on your computer, the raw data generated would be 334 miles wide.”

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.

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