Researchers from Cardiff University report the discovery of new links between the breakdown in brain cell development and the risk of schizophrenia and other psychiatric disorders.
Genetic risk factors are known to disrupt brain development in a number of these disorders, but little is known about which aspects of this process are affected. This research is the first time that genetic disruption of specific cell processes crucial to brain development has been linked to disease risk in a wide range of psychiatric disorders, according to the scientists who published their study (“Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants”) in Nature Communications.
“Coordinated programs of gene expression drive brain development. It is unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. We identify transcriptional programs expressed during early neurogenesis in vitro and in human fetal cortex that are down-regulated in DLG2−/− lines,” write the investigators.
“Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes. Neurogenic programs also overlap schizophrenia…pathways active during prenatal cortical development may also be associated with mature neuronal dysfunction.
“Our data from human embryonic stem cells, when combined with analysis of available fetal cortical gene expression data, de novo rare variants, and GWAS [genome wide association studies] statistics for neuropsychiatric disorders and cognition, reveal a convergence on transcriptional programs regulating excitatory cortical neurogenesis.”
The study was jointly led by Andrew Pocklington, PhD, from the division of psychological medicine and clinical neurosciences, and Eunju Jenny Shin, PhD, previous from the neuroscience and mental health research institute at Cardiff University, and now at Keele University.
“Genetic factors play a significant role in determining a person’s risk of developing psychiatric disorders. Uncovering biological processes impacted by these genetic risk factors is a major step towards understanding the causes of disease,” says Pocklington.
“To truly understand the root causes of psychiatric disorders, we focused on studying the development of brain cells,” adds Shin. “The knowledge gained through this approach may ultimately help guide the development of novel therapies or help explain why some individuals respond to some treatments but not others.”
The scientists studied the birth and early development of human brain cells (neurogenesis) in vitro using human pluripotent stem cells. They identified several sets of genes that are switched on during neurogenesis, both in vitro and in human fetal brain, with each set appearing to play a distinct functional role. The researchers showed that genetic risk factors contributing to schizophrenia and other psychiatric disorders were highly concentrated in these sets.
According to Shin, “In vitro experiments showed that when activation of these sets is disrupted, the shape, movement, and electrical activity of developing brain cells is altered, linking changes in these properties to disease.”
Disorders linked to disruption of these genes included both early onset conditions (developmental delay, autism, and ADHD) and those with a later onset (bipolar disorder, major depression) for which disruption of early brain development is not generally thought to play a significant role.
This raises the question of whether some of these genes, which are first switched on long before birth, remain active later in life and contribute to mature brain function, where they can potentially be targeted therapeutically.
“Previous studies have shown that genes active in mature brain cells are enriched for common genetic variants contributing to schizophrenia,” notes Pocklington. “Much of this enrichment was captured by the early developmental gene sets, which seem to contain a greater burden of common genetic risk factors.
“This suggests that some biological pathways first switched on in the early pre-natal brain may remain active in later life, with genetic variation in these pathways contributing to disease by disrupting both development and mature brain function.”
Further work is needed to map out the full range of developmental processes disrupted in different psychiatric disorders and explore their longer-term effects on the brain, he explains.
“Although much remains to be uncovered, our findings provide valuable insight into the developmental origins of psychiatric disorders such as schizophrenia,” says Shin.