BALTIMORE, MD. — Sept. 4, 2024 — Finding the genes that turn on and off to cause disease isn’t always as simple as in Huntington’s disease, in which one mutation in a single gene causes the rare disorder.
Schizophrenia, for example, results from genetic risk spread throughout the genome. That’s why, for 14 years, Lieber Institute researchers have been trying to find an approach that would enable doctors to prevent or treat the disease and its disparate risk genes.
A new paper from the laboratory of Lieber Institute Investigator Giulio Pergola, PhD, has brought scientists one step closer. The study, published Sept. 4 in Neuron, examines many recently published networks of genes that neighbor schizophrenia risk genes in the brain. The research finds these genes are guilty by association and, in fact, carry their own risk for schizophrenia. Read the paper.
The neighboring genes carry lower risk individually than the known risk genes—but as a network of many genes, they hold power in numbers, says Dr. Pergola. Scientists call this effect of genes influencing each other to increase disease risk trans-heritability.
“Previous research suggested that the genes responsible for schizophrenia are a manageable number—maybe 100 to 200,” he explains. “If those are in touch with a network of 20,000 genes, even though the genes’ influence is small, it is 100 times more than the key genes. There is risk outside what we think is the core, and this research is among the first to model how trans-heritability is channeled into networks.”
The findings are useful as scientists strive to identify genes that new drugs could target to prevent or treat schizophrenia, Dr. Pergola says. To avoid unwanted side effects, very targeted treatments would ideally affect only the gene or genes that carry risk and only in the brain, where schizophrenia develops. That’s why some of the most supported potentially causative genes do not make for attractive drug targets.
Genes that interest scientists for their role in schizophrenia risk often show up elsewhere in the body, such as in the heart. “We don’t want to target that gene because we want to cure the brain without affecting the heart,” Dr. Pergola says.
“If we target not the principal gene but other genes in its surroundings, the hope is that if these outside genes really exert influence, we can target those, and maybe that’s more innocuous and less dangerous to tamper with,” he explains.
Dr. Pergola’s team, including the paper’s first author, Lieber Institute postdoctoral fellow Christopher Borcuk, Ph.D., is working with the Institute’s drug discovery team to move the research forward. The findings of the published study seem to affect specific types of neurons, and the scientists hope to find out where in the cells schizophrenia genes and their neighbors meet and work together. They are also examining how the neighboring genes might affect the core schizophrenia risk genes.
“We are leveraging the variants in the surrounding genes to predict the expression of the risk genes,” he says. “Once we do that, it will help us understand which people have risk in certain particular genes. That will help a lot more with identifying subgroups of people who may need different treatments or meet different thresholds for early detection before onset.”