Psychiatric disorders often overlap and can make diagnosis difficult. Depression and anxiety, for example, can coexist and share symptoms. Schizophrenia and anorexia nervosa. Autism and attention deficit/hyperactivity disorder, too. But, why?
Life experiences, environment, and genetics can all influence psychiatric disorders, but much of it comes down to variations in our genetics. Over the past few years, scientists in the field of psychiatric genetics have found that there are common genetic threads that may be linking and causing coexisting psychiatric disorders.
In 2019, researchers at the Psychiatric Genomics Consortium, Harvard University, and the UNC School of Medicine identified 136 "hot spots" within the genome that are associated with eight psychiatric disorders. Among them, 109 hot spots were shared among multiple disorders, or "pleiotropic". However, it was not clear at the time how genetic variations within these hot spots differed from those that only have roles in only one disorder.
A new genetic study, led by Hyejung Won, PhD, associate professor in the Department of Genetics and the UNC Neuroscience Center, and Patrick Sullivan, MD, FRANZCP, the Yeargen Distinguished Professor of Psychiatry and Genetics, has successfully delineated the functional consequences of genetic variants into two groups. Their findings, which were published in Cell, suggest that pleiotropic variants may be optimal targets for treatment, due to their extended roles in development and sensitivity to change.
Hyejung Won, PhD
"Pleiotropy was traditionally viewed as a challenge because it complicates the classification of psychiatric disorders," said Won. "However, if we can understand the genetic basis of pleiotropy, it might allow us to develop treatments targeting these shared genetic factors, which could then help treat multiple psychiatric disorders with a common therapy."
The human genome acts as the body's operating manual, containing the instructions that helped us develop from a single cell into a whole person. However, everyone's genetic foundation is unique. There are specific regions of the genome that are prone to genetic variations.
Specific genetic variants can impact biological processes, like protein overproduction or altered synapse formation, affecting brain development and contributing to psychiatric disorder. Luckily, researchers are armed with tools to track these variants and learn more about the origins of disease.
Identifying Casual Genetic Variants
In 2019, an international team of researchers at the UNC School of Medicine and the Psychiatric Genomics Consortium conducted genome-wide association studies (GWAS) on eight disorders: autism spectrum disorder, attention deficit/hyperactivity disorder (ADD), schizophrenia, bipolar disorder, major depressive disorder, Tourette syndrome, obsessive-compulsive disorder (OCD), and anorexia nervosa, to better understand the shared genetic underpinnings between psychiatric disorders.
The analysis previously revealed 136 "hot spots" on the genome that have a causal effect on one or more of the eight psychiatric disorders. Of those, 109 of these locations were identical across more than one disorder.
As part of their latest study in Cell, Won and colleagues wanted to pry more information from the genetic variants embedded within these 136 "hot spots." Using a powerful technology, called a massively parallel reporter assay, they sought to determine which causal variants could be interfering with gene regulation.
Gene regulation controls how and when proteins are produced in the body, allowing the tiny machines to carry out a wide array of functions in the body. If certain variants are interfering with this important process, researchers can use that information to home in on the variants of interest and use them as new targets for treatment.
Researchers first took all 17,841 genetic variants from the 136 "hot spots" and inserted them into human neural cells to see how they acted in a living system. After putting the variants through the massively parallel reporter assay, researchers found that 683 of the 17,841 genetic variants had a measurable effect on gene regulation.
Pleiotropic Variants vs. Disorder-Specific Variants
The researchers then categorized the 683 variants into two groups: those shared across multiple disorders (pleiotropic variants) and those specific to a single disorder (disorder-specific variants). After dividing them into categories, researchers performed a tried-and-true scientific method: compare and contrast.
Pleiotropic variants were found to be more active and more sensitive to change compared to disorder-specific variants. Researchers noted that pleotropic variants were active for much longer during brain development, compared to disease-specific ones. This extended activity suggests that pleiotropic variants may be influencing multiple stages of neurodevelopment and potentially contributing to various observable traits and disorders.
Additionally, the genes affected by these pleiotropic variants appear to be more sensitive to changes, meaning disruptions in these genes could have a bigger impact on human health.
"The proteins produced by these genes are also highly connected to other proteins," said Won. "Changes to these proteins in particular could ripple through the network, potentially causing widespread effects on the brain."
These findings mark an important step toward understanding how genetics contributes to shared symptoms across psychiatric disorders. Targeting these variants, their associated genes, and pathways could pave the way for treatments that address multiple conditions at once.
Other researchers on the latest project include Adriana Beltran, PhD, associate professor of genetics, Jiseok Lee, PhD, Sool Lee, PhD, and Jessica McAfee.
