Distinct psychiatric disorders share common genomic factors more broadly than current thinking suggests, according to a genomic analysis led by researchers at the University of Colorado Boulder and Mass General Brigham. The research, published in Nature, analyzed data of more than one million people diagnosed with at least one of 14 psychiatric disorders, along with the genomic data of five million healthy controls and found that some disorders, though biologically different, may share genetic factors that underlie these disorders. These findings have broad implications for diagnosis, classification, and the development of new drugs for these conditions.
“Right now, we diagnose psychiatric disorders based on what we see in the room, and many people will be diagnosed with multiple disorders. That can be hard to treat and disheartening for patients,” said lead author Andrew Grotzinger, PhD, assistant professor of psychology and neuroscience at CU Boulder. “This work provides the best evidence yet that there may be things that we are currently giving different names to that are actually driven by the same biological processes.”
The study was conducted in collaboration with the international Psychiatric Genomics Consortium Cross-Disorder Working Group, an organization focused on fostering studies looking to better understand why many psychiatric conditions co-occur and have shown overlapping genetic risks. “Psychiatric disorders display high levels of comorbidity and genetic overlap, challenging current diagnostic boundaries,” the researchers wrote.
For this work, the investigators examined genome-wide association study (GWAS) data from 1,056,201 people diagnosed with at least one psychiatric disorder and more than five million individuals without any diagnoses. The disorders included both childhood- and adult-onset conditions such as schizophrenia, bipolar disorder, depression, anxiety, post-traumatic stress disorder, autism, attention-deficit/hyperactivity disorder, and substance use disorders.
Using the GWAS data the team characterized five genomic factors that explain the majority of the genetic variance of the individual disorders (about 66% on average). These factors corresponded to groups of conditions with shared genetic characteristics including compulsive disorders, internalizing disorders, substance use disorders, neurodevelopmental disorders, and a factor defined by schizophrenia and bipolar disorder.
In particular, the finding of the shared basis of schizophrenia and bipolar disorder differs from the long-standing thinking that they are two distinct conditions. In this study, the researchers showed that about 70% of the genetic signal associated with schizophrenia is also associated with bipolar disorder. “Genetically, we saw that they are more similar than they are unique,” Grotzinger said. According to the researchers, these disorders showed “high levels of polygenic overlap and local genetic correlation and very few disorder-specific loci.”
In addition to the genetic underpinnings of psychiatric disorders, the study also described some of the biological pathways that may underlie different groups of disorders. Genes expressed in excitatory neurons were enriched in the schizophrenia–bipolar factor, including neurons from adult and fetal brain data. In comparison, internalizing disorders such as major depression, PTSD, and anxiety were more consistently associated with oligodendrocytes and related glial cells, which help maintain the brain’s wiring.
In all, the team found widespread genetic overlap across all 14 disorders included in their study. At the genome-wide level, they identified 101 regions with correlated genetic effects, including a hotspot on chromosome 11 associated with eight disorders.
Prior research into psychiatric conditions has hinted at shared genetic risk factors. Rapid progress in psychiatric genomics has identified hundreds of loci with pleiotropic effects across disorders, and earlier cross-disorder analyses from the Psychiatric Genomics Consortium showed high correlations in genetic liability. The current study confirms many of these earlier findings and implications by using updated datasets, including a larger number of disorders, and triangulation across genome-wide, regional, functional, and individual-variant analyses.
While providing a more solid footing for the notion of shared molecular biology among psychiatric disorders, more research is needed before this information can be used to change how these disorders are diagnosed, though Grotzinger noted his hopes that could be used in future revisions to the Diagnostic and Statistical Manual of Mental Disorders. By identifying genetic features shared across disorders, the researchers said it could be possible to develop treatments that target multiple conditions simultaneously rather than addressing each separately.
Next steps in this line of research include broadening the analyses to more diverse, non-European populations which made of the bulk of the current study. The team also plans to explore how shared genetic pathways might guide the development or repurposing of therapies that address commonly co-occurring psychiatric conditions.
