Genetic Variants Synergize to Confer Schizophrenia Risk

The Context: Schizophrenia has a strong genetic component. Scientists have discovered many genetic variants that may play a role in its onset, but each individual variant can only explain a small fraction of the risk, and much of the disease’s genetic basis remains unexplained.

The Study: Interactions between certain genetic variants can increase one’s risk for schizophrenia, and stem cell models of the disease reveal the synergistic effects of these variants on gene regulation, finds a new study in Nature Genetics by NYSCF – Robertson Stem Cell Investigator and Associate Professor of Neuroscience, of Psychiatry, and of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai Dr. Kristen Brennand.

The Importance: Understanding the genetic contributions of schizophrenia will help researchers better predict who will get the disease and develop effective strategies for intervention.

Many genetic variants have been associated with schizophrenia through genome-wide association studies (GWAS), but how these different genetic variants lead to onset of the disease is not well understood. A new study in Nature Genetics by NYSCF – Robertson Stem Cell Investigator and Associate Professor of Neuroscience, Psychiatry, and Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai Dr. Kristen Brennand uses patient stem cells to discover that different ‘gene regulators’ — that is, genetic variants with an impact on gene regulation – work together to raise one’s risk for developing the disease.

Dr. Brennand’s team decided to focus on genetic variants associated with schizophrenia risk that were also implicated in regulating gene expression, a means by which they could increase disease risk. These gene regulators, also known as eQTLs, govern the expression of multiple genes. In their study, the researchers used neurons generated from patient stem cells to study regulators of four genes thought to play a role in schizophrenia. The team mimicked the interaction of these genes by increasing or decreasing their expression using the gene editing technique CRISPR (three had their expression increased, and one’s expression was decreased).

Manipulating the expression of the four risk genes in turn caused altered expression of more than a thousand other genes, a number far greater than if the genes had been acting alone.

“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 the National Institute of Mental Health in a press release. “Learning more about the downstream cellular and molecular effects of such synergy holds hope for advances in precision psychiatry and more personalized medicine.”

Some of the 1,261 additional affected genes carried variants linked to autism spectrum disorder or bipolar disorder, suggesting that the variants may have broader implications for mental health disorders beyond schizophrenia.

The induced gene expression changes found in the experiment were also found in post-mortem brains of patients with schizophrenia, autism spectrum disorder, and bipolar disorder as well as in stem cell models of a rare form of childhood-onset schizophrenia.

“This unexpected synergy between gene variants demonstrated how even subtle genetic variations can impact neuronal function,” said Dr. 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.”

Journal Article: 

Synergistic effects of common schizophrenia risk variants. 
Schrode N, Ho S-M, Yamamuro K, Dobbyn A, Huckins L, Matos MR. Cheng E, Deans PJM, Flaherty E, Barretto N, Topol A, Alganem K, Abadali S, Gregory J, Hoelzli E, Phatnani H, Singh V, Girish D, Aronow B, Mccullumsmith R, Hoffman GE, Stahl EA, Morishita H, Sklar P, Brennand KJ. Nature Genetics. 2019. DOI: 10.1038/s41588-019-0497-5