Some psychiatric disorders have many overlapping symptoms, which can make it very challenging to diagnose a specific disease. These disorders can be influenced by genetic factors, which may involve a variety of small changes in the sequences of many genes. These complicated genetic relationships can be difficult to decipher.
Scientists have found 136 genetic hotspots that are linked to eight different psychiatric disorders, which have some overlapping symptoms. Of these, 109 hotspots are shared by several disorders. Now scientists have revealed how these hotspots differ. The work has also shown that treatments may be more effective if they aim for genetic variations that are pleiotropic, or shared among multiple disorder. The findings have been reported in Cell.
"Pleiotropy was traditionally viewed as a challenge because it complicates the classification of psychiatric disorders," said senior study author Hyejung Won, PhD, an associate professor at the University of North Carolina. "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 eight disorders that were a focus of this work included autism spectrum disorder, attention deficit/hyperactivity disorder (ADD), anorexia nervosa, bipolar disorder, major depressive disorder, obsessive-compulsive disorder (OCD), schizophrenia, and Tourette syndrome.
In this study, the scientists wanted to identify the genetic variants that may be disrupting gene regulation, leading to an excess or loss of normal protein levels and potentially leading to these disorders. It may be possible to treat them by targeting those genetic variants.
There were 17,841 genetic variants within the 136 hotspots that were identified, and the researchers modeled these variants in human neurons. With technology called a massively parallel reporter assay, the researchers determined that 683 of the 17,841 genetic variants could alter gene regulation.
These 683 variants were categorized by whether they were common to multiple disorders, which are pleiotropic variants, or unique to one disorder.
There was more activity and sensitivity among the pleiotropic variants compared to variants that were specific to one disease. Pleotropic variants also had extended activity levels during development, which suggests that pleiotropic variants might affect different neurodevelopmental stages; this may be why they can influence the risk of more than one disorder.
"The proteins produced by these genes are also highly connected to other proteins," added Won. "Changes to these proteins in particular could ripple through the network, potentially causing widespread effects on the brain."
Sources: University of North Carolina at Chapel Hill School of Medicine, Cell
