Schizophrenia Genomics Study Looks for Somatic Mosaicism in Brain Cells
By Maxine Bookbinder
May 20, 2015 | The Lieber Institute for Brain Development (LIBD) announced a 5-year, $10.5 million grant from the National Institutes of Health (NIH) to support a first-of-its-kind multi-site, interdisciplinary project to research potentially non-inherited genetic causes of schizophrenia. By identifying the root biological origins now, more precise and effective therapies can be developed later.
The NIH awarded the grant to LIBD, The Salk Institute, and the University of Michigan, bringing together a collaboration of global leaders in genetics, neurodevelopmental biology, psychiatry, cell biology, and computational bioinformatics to investigate the role of non-inherited genetic mutations, or somatic mosaicism, in brain cells. Mosaicism is the presence of two or more genetically different cell lines in an individual or other organism.
“The hypothesis of this study is that somatic mosaicism plays a part in the cause of schizophrenia,” says Laura Wells, LIBD director of Public Affairs. “We know schizophrenia is inherited in part, but the genetics have proven to be very complex. The team in this project will, for the first time, systematically study the effect of somatic mosaicism in brain cells to see if there is an association with schizophrenia.” Somatic DNA copy number variations (CNVs) have been identified in multiple tissues from normal people, but have not been meticulously analyzed in brain tissues from individuals with psychiatric disorders. The study will examine whether there are more somatic variants in neurons in individuals with schizophrenia and will focus on non-inherited mutations, which can occur at random times in brain development.
LIBD will provide brain cells and living dura cells (the dense membrane that is closest to the skull) from individuals diagnosed with schizophrenia and an equal number from control samples from its extensive human brain bank, focusing on four regions of the brain associated with schizophrenia. It will conduct whole genome and RNA sequencing to confirm somatic variation in tissues and cells. The University of Michigan will lead efforts to characterize somatic mosaicism from the samples and, in later stages of the project, will functionally characterize the genetic variations in vivo in mouse models. The Salk Institute will lead efforts to identify somatic mosaicism with single cell analyses and later to functionally characterize identified genetic variations in vitro. All three facilities will work with the same biological samples.
The groups will share project results and compare genomic variation associated with brain and fibroblast samples from the same subjects in real time. Each principal investigator will deposit all sequence data into the project database; data from the Schizophrenia Genetics and Brain Somatic Mosaicism (BSM) Consortium will be managed according to the 2008 1000 Genomes Project recommendations. A Data Coordination Committee (DCC), consisting of at least one person from each of the three project teams, will manage and maintain the sites and ensure that data, analysis tools, and procedures are added to the database as quickly as possible. The DCC will lead efforts for technical data coordination and standardization within the larger BSM network, coordinate data submission to appropriate genome databases, and use wiki-style intranet resources to maintain updates and information about sample procurement and informatics pipelines.
By examining the cause of schizophrenia at this cellular level, investigators hope to eventually be able to treat the cause rather than only symptoms. According to Wells, research will guide development of more precise intervention strategies and may one day lead to new diagnostic tools to identify individuals most at risk for developing schizophrenia and other neuro-developmental disorders.
Schizophrenia is a medical condition, says Wells. Uncovering the root causes will enable more effective treatment and may help solve other mysteries surrounding the illness, such as whether it is possibly a spectrum disorder, given its varying characteristics and levels of severity. Research will also help clinicians characterize psychiatric illnesses based on biology.
“This is one of the most complex and least-understood illnesses,” says Wells. She hopes further support of research such as this will shed light on the vast array of unknowns that plague victims and puzzle the medical community.
Schizophrenia occurs in one percent of people globally, but in 10 percent in people with a first-degree relative. According to the NIMH, schizophrenics have a higher rate of joblessness and homelessness; fewer than 50% experience a sustained recovery. According to the Treatment Advocacy Center, about 10% of the American prison population, or about 230,000 individuals, have severe mental disorders and are in prison rather than psychiatric hospitals.