New genetic mutations shed light on schizophrenia

January 22, 2014 by Veronica Meade-Kelly, Broad Institute of MIT and Harvard
Functional magnetic resonance imaging (fMRI) and other brain imaging technologies allow for the study of differences in brain activity in people diagnosed with schizophrenia. The image shows two levels of the brain, with areas that were more active in healthy controls than in schizophrenia patients shown in orange, during an fMRI study of working memory. Credit: Kim J, Matthews NL, Park S./PLoS One.

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 , 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 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."

Explore further: Children of older dads more likely to suffer mental illness, study shows

More information: Purcell et al. "A polygenic burden of rare disruptive mutations in schizophrenia." Nature DOI: 10.1038/nature12975 . http://dx.doi.org/10.1038/nature12975

Fromer et al. "De novo mutations in schizophrenia implicate synaptic networks." Nature DOI: 10.1038/nature12929 . http://dx.doi.org/10.1038/nature12929

Related Stories

Children of older dads more likely to suffer mental illness, study shows

January 22, 2014
(Medical Xpress)—Children with older fathers are more susceptible to mental health disorders a University of Queensland (UQ) study has found.

Understanding Schizophrenia

November 16, 2011
(Medical Xpress) -- Genetic mutations that cause schizophrenia could be linked to systems in the brain responsible for learning and memory, a major University study suggests.

Team first to map autism-risk genes by function

November 21, 2013
Pity the poor autism researcher. Recent studies have linked hundreds of gene mutations scattered throughout the brain to increased autism risk. Where do you start?

Researchers shed light on role of genes in autism

June 14, 2013
(Medical Xpress)—Research carried out by Medical Research Council (MRC) researchers at the University of Oxford has uncovered a chain of genetic events that are common in individuals with autism, and have examined for the ...

Researchers uncover impact of mutations in the human genome on cognitive ability

December 19, 2013
deCODE genetics reported today in the journal Nature that mutations associated with an increased risk of schizophrenia and autism also affect cognition in individuals without the disease or intellectual disability. The research ...

Study reveals molecular networks of mental health disorders

February 27, 2013
(Medical Xpress)—Early diagnosis and intervention for ADHD, autism and schizophrenia could be made possible after Australian scientists discovered the molecular networks in the brain showing psychiatric and developmental ...

Recommended for you

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

The surprising role of gene architecture in cell fate decisions

January 16, 2018
Scientists read the code of life—the genome—as a sequence of letters, but now researchers have also started exploring its three-dimensional organisation. In a paper published in Nature Genetics, an interdisciplinary research ...

How incurable mitochondrial diseases strike previously unaffected families

January 15, 2018
Researchers have shown for the first time how children can inherit a severe - potentially fatal - mitochondrial disease from a healthy mother. The study, led by researchers from the MRC Mitochondrial Biology Unit at the University ...

Genes that aid spinal cord healing in lamprey also present in humans

January 15, 2018
Many of the genes involved in natural repair of the injured spinal cord of the lamprey are also active in the repair of the peripheral nervous system in mammals, according to a study by a collaborative group of scientists ...

The coming of age of gene therapy: A review of the past and path forward

January 11, 2018
After three decades of hopes tempered by setbacks, gene therapy—the process of treating a disease by modifying a person's DNA—is no longer the future of medicine, but is part of the present-day clinical treatment toolkit. ...

Large-scale study to pinpoint genes linked to obesity

January 10, 2018
It's not just diet and physical activity; your genes also determine how easily you lose or gain weight. In a study published in the January issue of Nature Genetics, researchers at the Icahn School of Medicine at Mount Sinai ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.