Gene expression regulators work together to raise an individual’s risk of developing schizophrenia, according to new research. Scientists used CRISPR to simultaneously increase or decrease expression of several schizophrenia-implicated genes. That altered expression of more than 1,250 other genes. The magnitude of this effect was such that it suggests an underlying mechanism that is synergistic rather than additive.
The researchers were led by Kristen Brennand, of the Icahn School of Medicine at Mount Sinai, New York City, their findings are reported in Nature Genetics.
“This unexpected synergy between gene variants demonstrated how even subtle genetic variations can impact neuronal function,” said Brennand. “These interactions emphasize the importance of considering the complex nature of schizophrenia and other psychiatric disorders, where a combination of gene variants contributes to disease.”
Past genome-wide association studies have revealed almost 150 chromosomal sites associated with increased risk for this condition. However, individually, each of these sites can explain only a small fraction of the risk. Even when the effects of disease-linked rare genetic variants are factored in, most of schizophrenia’s known high inheritance remains unexplained. However, it is known that more than 40% of the suspect chromosomal sites contain regulators, called expression quantitative trait loci, or eQTLs, that govern the expression of multiple genes.
“Individually, these gene regulators have a modest effect on the brain. Working in concert, they exert different and more significant effects on the brain — effects that boost schizophrenia risk,” explained David Panchision, chief of the Developmental Neurobiology Program at NIMH. “Learning more about the downstream cellular and molecular effects of such synergy holds hope for advances in precision psychiatry and more personalized medicine.”
Brennand and colleagues studied regulators in induced neurons using a molecular modeling technology that makes it possible to grow a person’s unique neurons in a petri dish using isogenic human induced pluripotent stem cellsderived from their skin cells. The researchers used the model to take a closer look at the downstream molecular consequences of gene expression changes known to occur in schizophrenia, and compared the effects in the cells on changes seen in postmortem brains and similarly modeled neurons of people with the illness. Specifically, they used CRISPR to mimic the interaction of multiple risk genes to simultaneously increase or decrease expression of one putative schizophrenia associated gene –SZ eQTL (FURIN rs4702) — and four schizophrenia-implicated genes known to harbor eQTLs — SZ eQTL genes (FURIN, SNAP91, TSNARE1 and CLCN3).
The researchers report that their platform resolves pre- and postsynaptic neuronal deficits, recapitulates genotype-dependent gene expression differences and identifies convergence downstream of SZ eQTL gene perturbations. “Our observations highlight the cell-type-specific effects of common variants and demonstrate a synergistic effect between SZ eQTL genes that converges on synaptic function,” they said. Adding that “We propose the links between rare and common variants implicated in psychiatric disease risk constitute a potentially generalizable phenomenon occurring more widely in complex genetic disorders.”