We use cookies to understand how you use our site and to improve your experience. This includes personalizing content and advertising. To learn more, click here. By continuing to use our site, you accept our use of cookies. Cookie Policy.

Features Partner Sites Information LinkXpress
Sign In
Advertise with Us
PURITAN MEDICAL

Download Mobile App




Events

ATTENTION: Due to the COVID-19 PANDEMIC, many events are being rescheduled for a later date, converted into virtual venues, or altogether cancelled. Please check with the event organizer or website prior to planning for any forthcoming event.

First-Ever Gene Identified with Biological Origin of Schizophrenia

By LabMedica International staff writers
Posted on 07 Feb 2016
Print article
Image:	Micrograph of imaging experiment showing C4 (green) located at the synapses (red and white) of cultured primary human neurons (cell bodies in blue) (Photo courtesy of Heather de Rivera, McCarroll Laboratory).
Image: Micrograph of imaging experiment showing C4 (green) located at the synapses (red and white) of cultured primary human neurons (cell bodies in blue) (Photo courtesy of Heather de Rivera, McCarroll Laboratory).
Image: Of over 100 chromosomal sites harboring known genetic risk for schizophrenia—the site in Chromosome 6 harboring the C4 gene towers far above other risk-associated areas on schizophrenia’s genomic “skyline,” marking the disease’s strongest known genetic region of influence (Photo courtesy of Psychiatric Genomics Consortium).
Image: Of over 100 chromosomal sites harboring known genetic risk for schizophrenia—the site in Chromosome 6 harboring the C4 gene towers far above other risk-associated areas on schizophrenia’s genomic “skyline,” marking the disease’s strongest known genetic region of influence (Photo courtesy of Psychiatric Genomics Consortium).
In a landmark study, researchers have identified mutants of the complement component 4 (C4) gene that are strongly associated with the risk of developing schizophrenia.

They further discovered that C4, the well-known immune system protein, is also involved in “synaptic pruning” in the brain. The study provides important insights into the biological origin and underlying physiology of this debilitating disease, and likely a new path for developing early-detection diagnostic tests as well as more effective drugs for treatment and prevention—by allowing therapeutic strategies to be directed at the disorder’s roots, rather than its symptoms.

“Since schizophrenia was first described over a century ago, its underlying biology has been a black box, in part because it has been virtually impossible to model the disorder in cells or animals,” said study leader Steven McCarroll, associate professor at Harvard Medical School and director of genetics for the Stanley Center for Psychiatric Research at the Broad Institute (Cambridge, MA, USA), “The human genome is providing a powerful new way in to this disease.”

Previously, over 100 regions in the human genome were identified that carry risk factors for schizophrenia. The strongest risk-association signal was by far on chromosome 6, in a region long associated with infectious disease, causing some to suggest that schizophrenia might be triggered by an infectious agent. Schizophrenia’s strongest known genetic association at a population level involves variation in the immune-system’s major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have remained elusive using conventional genetic methods. The new study shows that this association arises in part from many diverse alleles of the C4 genes. By examining RNA levels, the researchers found that these alleles generated widely varying C4A and C4B expression levels in the brain.

The study was based on DNA collected from over 100,000 people from 30 countries, detailed analysis of complex genetic variation in more than 65,000 human genomes, development of an innovative analytical strategy, examination of postmortem brain samples from hundreds of people, and the use of animal models to further study biological function of C4.

Analysis of genome data of nearly 65,000 people (with and without schizophrenia) revealed a striking correlation: patients who had particular C4 alleles showed higher expression of that allele, as well as higher risk of developing schizophrenia. So mutations leading to abnormal overexpression of C4 were strongly associated with predisposition to schizophrenia.

How does C4—known to mark infectious microbes for destruction by immune cells—affect the risk of schizophrenia? The researchers found that human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. They also discovered that C4 plays a key role in pruning synapses during brain maturation. In particular, C4 was necessary for complement component 3 (C3) to be deposited onto synapses, as a tag signaling that those synapses should be pruned. The data also suggested that higher C4 activity is associated with increased elimination of brain synapses at a key period in brain development. In mice, C4 mediated synapse elimination during postnatal development.

The human brain normally undergoes widespread synapse pruning (especially in the cerebral cortex) during adolescence, the typical period of symptoms onset. “Normally, pruning gets rid of excess connections we no longer need, streamlining our brain for optimal performance, but too much pruning can impair mental function,” explained Thomas Lehner, PhD, director, Office of Genomics Research Coordination of the NIH’s National Institute of Mental Health (NIMH; Bethesda, MD, USA), “It could help explain schizophrenia’s delayed age-of-onset of symptoms in late adolescence/early adulthood and shrinkage of the brain’s working tissue.” The findings may also help explain the longstanding mystery of why brains from people with schizophrenia tend to have a thinner cerebral cortex with fewer synapses than unaffected individuals.

The results revealed that excessive pruning of brain synapse connections predisposes to schizophrenia. The fortunate fact that much is already known about the role of C4 and other complement proteins in the immune system means that researchers can tap into a wealth of existing knowledge to identify possible therapeutic approaches. For example, anti-complement drugs are already under development for treating other diseases.

“While it’s still early days, we’ve seen the power of understanding the biological mechanism of disease in other settings,” said Eric Lander, director of the Broad Institute, “Understanding schizophrenia will similarly accelerate progress against this devastating disease that strikes young people.”

The work was enabled in large part by catalytic funding from the Stanley Center and the paper has been dedicated to the late Ted Stanley. “Through philanthropy, we have been able to take bets on risky science with potentially transformative results,” said Stanley Center director Steven Hyman, “With support from the late Ted and Vada Stanley, Broad scientists have the freedom to bring together people, capabilities, and resources in innovative ways.”

“This study marks a crucial turning point in the fight against mental illness. It changes the game,” added Bruce Cuthbert, PhD, acting NIMH director, “Thanks to this genetic breakthrough we can finally see the potential for clinical tests, early detection, new treatments, and even prevention.”

The study, by Sekar A et al., was published online ahead of print November 27, 2016, in the journal Nature.

Related Links:

Broad Institute
[US] National Institute of Mental Health (NIMH)
More about the study


Flocked Swab
HydraFlock and PurFlock Ultra
Gold Supplier
Automatic Western Blot Analyzer
Tenfly Phoenix Blot Analyzer
New
Gold Supplier
CLIA Analyzer
VIRCLIA
New
Semi-Automatic Coagulation Analyzer
Clot 2B

Print article

Channels

Clinical Chem.

view channel
Image: Electrochemical cells etched by laser on wooden tongue depressor measure glucose and nitrite in saliva (Photo courtesy of Analytical Chemistry)

Biosensor-Fabricated Wooden Tongue Depressor Measures Glucose and Nitrite in Saliva

Physicians often use tongue depressors to examine a patient's mouth and throat. However, it is hard to imagine that this simple wooden tool could actively assess a patient's health. This idea has led to... Read more

Hematology

view channel
Image: The Atellica HEMA 570 and 580 hematology analyzers remove workflow barriers (Photo courtesy of Siemens)

Next-Gen Hematology Analyzers Eliminate Workflow Roadblocks and Achieve Fast Throughput

Hematology testing is a critical aspect of patient care, utilized to establish a patient's health baseline, track treatment progress, or guide timely modifications to care. However, increasing constraints... Read more

Immunology

view channel
Image: Newly observed anti-FSP antibodies have also been found to predict immune-related adverse events (Photo courtesy of Calviri)

First Blood-Based Biomarkers Test to Predict Treatment Response in Cancer Patients

Every year worldwide, lung cancer afflicts over two million individuals and almost the same number of people succumb to the disease. This malignancy leads the charts in cancer-related mortalities, with... Read more

Microbiology

view channel
Image: The rapid MTB strip test for tuberculosis can identify TB patients within two hours (Photo courtesy of Chulalongkorn University)

Rapid MTB Strip Test Detects Tuberculosis in Less Than an Hour without Special Tools

Tuberculosis (TB), a highly infectious disease, continues to pose significant challenges to public health worldwide. TB is caused by a bacterium known as "Mycobacterium tuberculosis," spreading through... Read more

Pathology

view channel
Image: The UNIQO 160 (CE-IVDR) advances diagnostic analysis for autoimmune diseases (Photo courtesy of EUROIMMUN)

Novel Automated IIFT System Enables Cutting-Edge Diagnostic Analysis

A newly-launched automated indirect immunofluorescence test (IIFT) system for autoimmune disease diagnostics offers an all-in-one solution to enhance the efficiency of the complete IIFT process, comprising... Read more

Technology

view channel
Electronic biosensor uses DNA aptamers for detecting biomarkers in whole blood samples (Photo courtesy of Freepik)

Electronic Biosensor Detects Biomarkers in Whole Blood Samples without Addition of Reagents

The absence of robust, reliable, and user-friendly bioanalytical tools for early and timely diagnosis of cardiovascular diseases, particularly sudden cardiac arrest, leads to preventable deaths and imposes... Read more

Industry

view channel
Image: The Coris acquisition provides Avacta with a broad, professional-use rapid test product portfolio (Photo courtesy of Coris Bioconcept)

Avacta Expands Diagnostics Portfolio with Acquisition of Rapid Test Maker Coris Bioconcept

Avacta Group plc (London, UK), a life sciences company developing oncology drugs and diagnostics, has acquired Coris Bioconcept SRL (Gembloux, Belgium) for an upfront cash consideration of GBP 7.... Read more
Copyright © 2000-2023 Globetech Media. All rights reserved.