Identifying new risk genes for schizophrenia

Schizophrenia, a psychiatric disorder that affects how a person feels, thinks, and behaves, affects roughly 1% of the population (approximately 3.5 million people in the U.S.) and is a leading cause of disability and death. It has a strong genetic component, with an estimated heritability of about 80%. Heritability measures how closely the differences in people’s genes account for differences in their manifested traits.

Identifying risk-associated genes is key to enabling drug development for schizophrenia. Genetic research thus far has focused on the genes that have the biggest effect on a person’s risk.

However, although more than 200 loci—specific locations on a chromosome—have been tied to schizophrenia risk using a genetic research tool called GWAS, researchers estimate that more than 1,000 genes are involved in the condition, which suggests that many risk-related genes remain undetected.

In a paper published in Advanced Science, the lab of Bingshan Li, professor of molecular physiology and biophysics, changed the parameters for how to identify a risk gene from GWAS loci and looked for “weaker” signals.

They found that dysfunction in two biological processes, the development and morphology of dendrites or neuronal projections, play a role in the disorder. The paper is titled “Analyses of GWAS and Sub-Threshold Loci Lead to the Discovery of Dendrite Development and Morphology Dysfunction Underlying Schizophrenia Genetic Risk.”

Rui Chen, a research instructor in molecular physiology and biophysics and one of the study’s three first authors, discussed the research.

Chen’s co-first authors were research instructor of molecular physiology and biophysics Quan Wang, and Emory University researcher Benjamin Siciliano from collaborator Zhexing Wen’s lab.

What issue/problem does your research address?

Even though large genetic studies show that schizophrenia is strongly influenced by DNA, the usual analyses miss many weaker—but meaningful—signals and don’t clearly point to what’s going wrong in the brain.

Our study looks beyond the standard cut-off to include these “near-miss” genetic clues and finds a common thread: problems in how neurons grow and shape their dendrites, “branches” that are essential for communication in the brain.

We confirmed in human induced pluripotent stem cell–derived neurons that increasing the expression levels of two implicated genes disrupts neuron dendrite growth. This points to a tangible biological pathway—and potential treatment target—linking genetic risk to the pathogenesis of schizophrenia.

What was unique about your approach to the research?

Most genetic studies of schizophrenia focus only on the strongest signals. We took a different route by also looking at the many genetic signals that almost but don’t quite reach the usual threshold for discovery.

By developing a rigorous way to integrate these sub-threshold signals with the traditional ones, we uncovered hidden patterns that would otherwise have remained invisible.

This expanded approach led us to a new biological pathway—the one controlling how brain neurons grow and branch their connections—that had not been thought relevant before. We confirmed these findings directly in human iPSC-derived neurons, linking the genetics of schizophrenia to neuron morphological changes in the developing brain.

This work was possible because of Vanderbilt’s unique strengths in genetics and neuroscience. Our team combined expertise from the Vanderbilt Genetics Institute and the Department of Molecular Physiology and Biophysics, both of which specialize in developing powerful statistical and computational tools to make sense of complex genetic data.

Vanderbilt also fosters strong collaborations across psychiatry, molecular biology, and bioinformatics, which enabled us to bridge large-scale data analysis with experimental validation. This cross-disciplinary environment, together with access to leading experts and resources, made Vanderbilt an ideal place to push the boundaries of schizophrenia genetics research.

What were your top three findings?

1. Hidden genetic clues matter: By looking beyond only the strongest genetic signals, we discovered that many “near-miss” genetic changes that carry important information about the genetic risk for schizophrenia.
2. Neuron dendrite morphogenesis is key to schizophrenia: The hidden genetic signals we identified pointed us to the pathway that directs how brain cells grow and branch out their connections (dendrites), showing that disrupted neuron dendritic morphogenesis in the brain may be a key driver of schizophrenia.
3. iPSC modeling confirms abnormal dendritic morphogenesis: When testing two of the near-miss genes (DCC and CUL7) in human induced pluripotent stem cell–derived neurons, we saw that increasing their expression caused the neurons to grow shorter and fewer branches, directly linking genetic risk to real changes in brain structure.

What do you hope will be achieved with the research results in the short term?

In the short term, we hope our results will help researchers and clinicians see schizophrenia in a new light—not just as a “chemical imbalance,” but also as a disorder of how brain cells connect and communicate.

By highlighting dendritic development as a new pathway involved in schizophrenia, our findings give scientists a concrete set of genes and biological processes to investigate further. This could guide follow-up studies, inspire new experimental models, and spark early efforts to identify drug targets aimed at protecting or restoring healthy brain cell connections.

What are your highest translational/clinical aspirations that might come from this research?

Our highest aspiration is that this work opens the door to new treatments that go beyond symptom control and address the root biology of schizophrenia.

By pinpointing specific genes and pathways that disrupt how brain cells form their branches and connections, we hope to guide the development of therapies that can protect or restore these processes. In the long run, this could mean:

• New drug targets focused on improving brain cell connectivity rather than only regulating brain chemicals,
• Precision psychiatry approaches where genetic information helps match patients to the most effective treatment strategies, and/or
• Preventive strategies that may one day reduce risk or delay onset in people with a strong genetic predisposition.

Who or what made the difference in your research?

This project came together because of the unique mix of people and resources around us. Our colleagues at Vanderbilt and partner institutions brought different kinds of expertise—statistical genetics, psychiatry, molecular biology, and stem-cell neuroscience—that we needed to connect big-data discoveries with lab validation.

We are particularly thankful to Zhexing Wen for leading the human iPSC experiments and our colleagues Xue Zhong and Nancy Cox at the Vanderbilt Genetics Institute for their critical contributions.

What small things helped along the way?

Behind the scenes, it was the little things that made the big difference. We couldn’t have done it without close teamwork between labs, endless brainstorming sessions, and our persistence across the years.

Where is this research taking you next?

We will be using new and larger genetic datasets to uncover additional schizophrenia risk genes and pathways that have not yet been detected. In addition, we plan to delve deeper into how schizophrenia risk genes affect brain cell connection changes over the course of brain development.

By tracing these pathways, we hope to identify new genes and their implicated neural cells that lead to abnormal brain development. The insights could be used either to predict disease at earlier stages or to intervene with treatments that change the course of illness.