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Cardiff University researchers report they have discovered a new link between disorders in the development of brain cells and the risk of schizophrenia and other mental illnesses
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Genetic risk factors are known to interfere with brain development in many of these disorders, but little is known about which aspects of this process are affected
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The study is the first to show that genetic disruption of specific cellular processes critical to brain development is associated with risk for various psychiatric disorders, according to a study by scientists published in the journal Nature Communications
"Coordinated programs of gene expression drive brain development
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It is unclear which transcriptional programs and cell types are affected in neuropsychiatric disorders such as schizophrenia
Downregulation affects neuronal differentiation and maturation, impairing migration, morphology, and action potential generation
.
Genetic variants in these programs have been associated with neuropsychiatric disorders and cognitive function, with associated variants concentrated in loss-of-function intolerance genes
"Our data from human embryonic stem cells, combined with existing fetal cortical gene expression data, de novo rare variants, and GWAS (genome-wide association studies) statistical analysis of neuropsychiatric disease and cognition, reveal the modulation of excitatory cortical neurogenesis Convergence of transcriptional programs
.
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The research was co-led by Dr Andrew Pocklington from the Department of Psychological Medicine and Clinical Neuroscience and Dr Eunju Jenny Shin, who worked at Cardiff University's Institute of Neuroscience and Mental Health and is now at Keele University
.
"Genetic factors play an important role in determining a person's risk of developing mental illness
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Uncovering the biological processes that are affected by these genetic risk factors is an important step in understanding the causes of disease," Pocklington said
"To really understand the root causes of mental illness, we focused on the development of brain cells," Shin added
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"The knowledge gained through this approach may ultimately help guide the development of new treatments, or help explain why some people respond to certain therapies and others do not
They found several sets of genes that are activated during neurogenesisin vitro and in the human fetal brain, each of which appears to play a different functional role
According to Shin, "In vitro experiments have shown that when the activation of these assemblies is disrupted, the shape, movement, and electrical activity of developing brain cells are altered, linking changes in these properties to disease
.
"
Disorders associated with disruption of these genes include both early-onset conditions (developmental delay, autism, and ADHD) and those with later-onset conditions (bipolar disorder, major depressive disorder), where disruption of early brain development is generally not thought to be an important factor
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This raises the question of whether some of these genes are activated long before birth, remain active later in life, and contribute to the maturation of brain function that could potentially be targeted for therapy
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"Previous research has shown that genes that are active in mature brain cells are enriched for common genetic variants that contribute to schizophrenia," Pocklington said
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"This enrichment was found in a large fraction of early developmental genomes that appear to contain a greater burden of shared genetic risk factors
"This suggests that some biological pathways that are initiated early in the prenatal period may remain active later in life, and that genetic variation in these pathways contributes to disease by disrupting developing and maturing brain function
.
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He explained that further work is needed to map the full spectrum of developmental processes that are disrupted in different psychiatric disorders and to explore their long-term effects on the brain
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"While much remains to be discovered, our findings provide valuable insights into the developmental origins of psychiatric disorders such as schizophrenia," Shin said
.
Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants
