Uncovering The Genetic Roots of Schizophrenia Using 3D Chromosome-mapping

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In a rare and interesting study, researchers from the University of California at Los Angeles have come one step closer to understanding the biology of schizophrenia.

Schizophrenia, a mental illness that affects about 1% of the human population worldwide has symptoms that include hallucinations, delusions and cognitive problems. It is a highly disabling condition and can drastically affect daily life.

Until now, the complex nature of the disease and the moderately lower occurrence rate has impeded the research on the study of the true cause of the disease. The current treatments for the disease only address the symptoms and do not cure the disorder.

The cause of the disease has a genetic basis wherein it is widely reported as being inherited from parent to offspring and often runs in families.

In the study, scientists have found dozens of genes and two major biological pathways that maybe involved in the development of the disorder by using a newly developed technology for analyzing DNA. It is worthy to note that this discovery has not been uncovered in the previous genetic studies of the disorder.

“This work provides a ROADMAP for understanding how common genetic variation associated with a complex disease affects specific genes and pathways,” said principal investigator Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and professor of neurology and psychiatry at UCLA’s David Geffen School of Medicine at UCLA.

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Earlier, a large genome-wide association study linked the disorder to small variations in DNA at more than 100 locations on the human genome. However, most of the variations lie in the regions of DNA that are not actually encoded or more simply, these regions lie outside genes. These results appeared puzzling to scientists as they could not put a finger on how these variations could actually have an impact on the functioning genes.

However in some cases, the non-gene locations identified in these studies have turned out to be what are known as “regulatory regions” which serve to enhance or repress the activity of genes lying near them on the genome. But many of the disease-linked regions had no obvious gene target nearby on the genome.

Dr. Daniel Geschwind, UCLA
Dr. Daniel Geschwind, UCLA

Geschwind and his team speculated the possibility that these disease linked regions would also serve a regulatory function but to genes that were farther away from their 2-dimensional locations. And the only way they could serve as such regulators would be if they come in close proximity to the genes they control if they are in such a 3-dimensional conformation that allows interaction, just as two opposite ends of a rope can end up close together when the rope is coiled.

This “3-dimensional proximity” can be easily aided by the packaging of DNA into chromosome that is usually how our genetic material exists in the cell.

To investigate that possibility, Geschwind and his team used a relatively new, high-resolution version of a technology called “chromosome conformation capture,” which chemically marks and then maps the locations where loops of chromosomal DNA come into contact.

The researchers applied the technique to map the immature human brain cells from the cortex as schizophrenia is believed to be a disorder of abnormal cortical development.

The mapping revealed that most of schizophrenia-linked sites from the earlier studies, contact known genes during brain development. Many of these are genes that have already been linked to schizophrenia in previous studies and the others had been suspected of involvement.

The genes newly linked to schizophrenia in this study include several for brain cell receptors that are activated by the neurotransmitter acetylcholine, implying that variations in the functions of these receptors can help bring about schizophrenia.

“There’s a lot of clinical and pharmacological data suggesting that changes in acetylcholine signaling in the brain can worsen schizophrenia symptoms, but until now there’s been no genetic evidence that it can help cause the disorder,” Geschwind said.

The analysis also pointed for the first time to several genes that are involved in the early-life burst of brain cell production that gives rise to the cerebral cortex of humans.

The findings of the study are published online in Nature and serve as the first-of-its-kind study wherein the genetic cues of a disease have been identified by 3-D chromosome mapping technology. This study also serves as an example for investigating other elusive genetic diseases

Source: ucla newsroom