In a study incorporating genetic data from more than 125,000 people, researchers have implicated 10 new genes in the development of schizophrenia.
One of the largest such studies ever, the project was part of the Schizophrenia Exome Sequencing Meta-Analysis Consortium and conducted by Tarjinder Singh, PhD, a postdoctoral fellow affiliated with the Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard, Massachusetts General Hospital, and Harvard Medical School, and colleagues. It was presented as a featured plenary presentation at the American Society of Human Genetics 2019 Annual Meeting in Houston, Texas.
Below, Dr. Singh explains how the research was conducted, the importance of the findings, and how they could inform future work in the field.
Q: What prompted you and your co-investigators to research the genetic underpinnings of schizophrenia?
There has been challenges in developing new medicines for schizophrenia, in part because we don't really understand how it develops. Past research has demonstrated that both genetics and the environment contribute to disease risk. While there are different approaches to studying schizophrenia and how it develops, we chose to look at genetic factors that predispose individuals to risk, and use that to learn more about the biology that underlies the condition.
Q: Please briefly describe your study and its findings.
As part of the Schizophrenia Exome Sequencing Meta-Analysis Consortium, we analyzed the DNA sequence of 25,000 people with schizophrenia and 100,000 people without the condition to identify risk genes for schizophrenia. In particular, we focused on genetic differences that disrupt protein-coding genes, which are very rare in the general population given how strongly they are selected against in every generation.
Through this work, we implicated 10 genes in which disruptions in the protein-coding sequence dramatically increase schizophrenia risk. Two of the 10 genes are coded for glutamate receptors, known to be important in communication between brain cells. Our findings suggest that decreased function of these receptors increases the individual risk for schizophrenia, and that studying them further, along with the other associated genes, can teach us more about how the condition develops.
Q: Were any of the outcomes particularly surprising to the study team?
We compared the genetic signal in schizophrenia to other neurodevelopmental and autism spectrum disorders, and found that some genes are more specific to schizophrenia and others are more shared across diagnoses. By comparing these data sets and conditions, we are learning how specific these risk genes are for schizophrenia, and about their wider clinical and biological consequences.
Q: What are the possible real-world applications of these findings in clinical practice?
I see these findings as an important but early step to learning more about the biology underlying schizophrenia. The end goal is to use these findings to design experiments which will help us better clarify the mechanisms of disease, and motivate the development of new and better therapies.
Q: Do you and your co-investigators intend to expand upon this research?
It is clear from this initial work that there are many more risk genes to be discovered, and that we are still in the early phases of gene discovery for schizophrenia. With a growing group of international collaborators, we hope to scale up this research and push towards a more complete genetic picture of schizophrenia.
Q: Is there anything else pertaining to your research and findings that you would like to add?
This kind of work—where tens of thousands of individuals are part of a study—is only possible through global collaborations between universities and institutes from around the world. It is really exciting and motivating to be part of a large team that is passionate and dedicated to better understanding mental illnesses and working towards better therapies.
Tarjinder Singh, PhD, is a postdoctoral fellow in the Analytic and Translational Genetics Unit at Massachusetts General Hospital, Harvard Medical School, and the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and MIT. He completed his PhD in 2017 at the Wellcome Sanger Institute and the University of Cambridge, United Kingdom, where he studied the role of rare variation in the genetic architecture of psychiatric and neurodevelopmental disorders with Dr. Jeffrey Barrett. Mentored by Dr. Mark Daly and in close collaboration with Dr. Benjamin Neale’s group, he currently works on the meta-analyses of sequencing data in psychiatric traits, with a primary focus on gene discovery in schizophrenia.
Singh T, Neale BM, Daly MJ, et al. Exome sequencing of 25,000 schizophrenia cases and 100,000 controls implicates 10 risk genes, and provides insight into shared and distinct genetic risk and biology with other neurodevelopmental disorders. Abstract presented at the American Society of Human Genetics 2019 Annual Meeting: Oct. 15, 2019; Houston, TX.