Scientists shed new light on the shared genetic basis of psychiatric disorders

Scientists have discovered a set of shared genetic variations that affect how the brain develops and increase the risk for several psychiatric disorders, including autism, depression, and schizophrenia. This important finding suggests that by targeting these common genetic factors, we might be able to develop treatments that could help people with a range of mental health conditions. The research has been published in the journal Cell.

Conditions like depression, anxiety, schizophrenia, anorexia nervosa, autism, and attention deficit/hyperactivity disorder often occur together, and their symptoms can overlap, making accurate diagnosis and effective treatment challenging. For example, someone struggling with depression might also experience anxiety, and distinguishing between the two, or understanding how they interact, can be difficult. Scientists have long known that a mix of life experiences, environmental factors, and a person’s genetic makeup contribute to these disorders. However, a significant portion of the puzzle lies in the subtle variations within our genes.

In recent years, the field of psychiatric genetics has made strides in uncovering common genetic threads that may underlie the coexistence of different psychiatric disorders. Previous research, notably a large-scale effort by the Psychiatric Genomics Consortium and other institutions in 2019, identified 136 regions in our genetic code that are linked to eight major psychiatric disorders. Within these regions, they found 109 “hot spots” that were associated with more than one disorder, a phenomenon called pleiotropy.

This meant that variations in these genetic hot spots could increase the risk for multiple conditions. However, at that time, it remained unclear how the genetic variations within these shared hot spots differed from genetic variations that were specific to just one disorder. Scientists wanted to understand if there was something unique about these pleiotropic variations that made them influential across several conditions.

Understanding the differences between pleiotropic and disorder-specific genetic variations could point towards new ways to treat these complex conditions. As researcher Jessica C. McAfee, a PhD student at UNC Chapel Hill explained, “I have many people in my life that are/were deeply affected by psychiatric disorders. Until recently, psychiatric disorders were understudied due to social stigmas. I think it is important to contribute to this type of science so we can both better understand these folk’s experiences and to better help them live their best lives.”

The researchers used a sophisticated technique called a massively parallel reporter assay to investigate the activity of thousands of genetic variations at once. This method allowed them to test how these variations influence gene regulation, which is the process that controls when and how genes are turned on or off. They focused on over 17,000 genetic variations that had previously been linked to the eight psychiatric disorders in the earlier large-scale study. These variations were located within the identified genetic hot spots.

The researchers created a library of DNA segments, each containing one of the genetic variations they were interested in. They placed these segments in front of a reporter gene, which acts like a light switch that turns on when the genetic segment is active in regulating genes. This entire construct was then introduced into human neural progenitor cells, which are early brain cells that can develop into different types of brain cells. By using neural progenitor cells, the researchers could study the effects of these genetic variations in a relevant cellular context for brain development.

After allowing time for the cells to process the DNA segments, the researchers measured the activity of the reporter gene. If a genetic variation increased the reporter gene’s activity, it indicated that the variation had a regulatory effect, meaning it could influence the activity of nearby genes in the brain. By comparing the activity of the reporter gene for different genetic variations, the researchers could identify which variations had the most significant impact on gene regulation. To ensure the reliability of their results, they repeated the experiment multiple times and included control DNA sequences for comparison.

In addition to the reporter assay, the researchers used CRISPR technology to further validate their findings. CRISPR is a gene editing tool that allows scientists to precisely alter specific DNA sequences in cells. They used CRISPR in neurons derived from human induced pluripotent stem cells, which are cells that can be reprogrammed to become any type of cell in the body, including neurons. By using CRISPR, they could directly manipulate specific genetic regions in neurons and observe the effects on gene expression.

Jiseok Lee, a postdoctoral research associate at UNC Chapel Hill, explained the advancement in technology: “Years ago, I could only perturb one gene of interest at a time in a mouse model, whereas nowadays with the advance of CRISPR and single-cell sequencing technologies, I can perturb dozens of genes simultaneously to study the outcome with cell type-specific resolution. I wanted to apply this cutting-edge, high-throughput methods to study the effects of genes linked to psychiatric disorders to gain insight into the disease mechanisms.”

The researchers found that about 9% of the genetic regions they tested showed significant enhancer activity, meaning they could boost the activity of genes. Interestingly, many of these active regions were located within repetitive DNA sequences called Alu repeats. These Alu repeats had not been extensively studied in the context of gene regulation before, but this study suggested they might play a more important role than previously thought.

Importantly, the study found that genetic variations linked to multiple disorders (pleiotropic variants) are different from those linked to a single disorder (disorder-specific variants). Pleiotropic variants tend to affect regions of DNA that are active in a wider variety of brain cell types during development. This means they have a broader influence on how the brain is built and how genes are regulated. In contrast, disorder-specific variants seem to have a more limited impact, potentially affecting fewer cell types or specific developmental stages. This difference in scope helps explain why some genetic variations increase the risk for multiple psychiatric disorders, while others are more specific to one condition.

These pleiotropic genetic variations often influence the activity of key regulatory proteins called transcription factors, which control the activity of many genes. The transcription factors affected by pleiotropic variants are highly connected within networks of interacting proteins, suggesting that changes in these factors can have widespread effects throughout the cell. The genes influenced by these pleiotropic variations are involved in fundamental brain processes and are expressed in many different types of brain cells.

“Genetic variants involved in multiple psychiatric disorders exert their effect at many different levels (gene/protein networks upstream and downstream of the variant),” Lee told PsyPost. “Compared to variants linked to single disorders, cross-disorder variants tend to affect a broader range of cell types and protein networks. When comparing single disorder versus multiple disorders, it’s not simply the number of affected genes that matters. Rather, it’s the interconnection of genes. Cross-disorder variants tend to affect proteins with more dense networks.”

This research points towards the possibility of developing treatments that target these shared genetic mechanisms, potentially offering relief for individuals struggling with a range of overlapping psychiatric disorders. “Perhaps the key takeaway from this study is that there are different genetic properties between genetics that are shared by multiple disorders vs genetics that are more specific to just one disorders,” McAfee said.

The researchers acknowledge some limitations to their study. While they validated some gene-variant connections with CRISPR, this validation was limited to a small number of examples. Future research is needed to comprehensively map all the gene targets of these genetic variations and to fully understand the mechanisms by which they contribute to psychiatric disorders. Additionally, the set of disorder-specific variants was mainly composed of variants related to schizophrenia because of the larger amount of genetic data available for schizophrenia compared to some other disorders.

“We need more examples to generalize our findings, but still our work provides an important proof-of-concept that genes affecting multiple disorders tend to affect more various cell types and have more strongly interconnected networks,” Lee explained.

Future studies could investigate the specific biological functions of the identified genes and protein networks to uncover potential targets for new treatments and to understand how these genetic variations influence symptoms and contribute to the development of psychiatric disorders.

“This project was an enormous collective effort from many people,” McAfee said. “It would not have been possible without incredible communication and teamwork. I have been lucky to work with such fantastic people.”

“This paper was an extensively collaborative work involving many wet-lab and dry-lab (computational) scientists,” Lee added. “For large-scale functional genomics studies like this, I find it nearly impossible for one person to perform everything. I learned how fortunate it is to have friendly, supportive coworkers with each one’s own strength and expertise! After all, it is the people who do science – and this is why we work together.”

The study, “Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders,” was authored by Sool Lee, Jessica C. McAfee, Jiseok Lee, Alejandro Gomez, Austin T. Ledford, Declan Clarke, Hyunggyu Min, Mark B. Gerstein, Alan P. Boyle, Patrick F. Sullivan, Adriana S. Beltran, and Hyejung Won.