A large international team of scientists is shedding new light on a long-standing puzzle in mental health: why many people are diagnosed with more than one psychiatric disorder over their lifetime. In research published December 10 in the journal Nature, the group presents the most extensive and detailed investigation so far into the shared genetic foundations of 14 psychiatric conditions.
The work was led by the Psychiatric Genomics Consortium’s Cross-Disorder Working Group. The group is co-chaired by Kenneth Kendler, M.D., a professor in the Department of Psychiatry at Virginia Commonwealth University’s School of Medicine, and Jordan Smoller, M.D., a professor in the Department of Psychiatry at Harvard Medical School.
Genetics and the Challenge of Defining Mental Illness
For most people diagnosed with a psychiatric disorder, that diagnosis is rarely the only one they will receive. Many go on to develop a second or even third condition, which complicates how mental illnesses are classified and treated. Life experiences and environment clearly shape mental health risk, but genetics also play an important role in determining why disorders so often overlap.
To better understand those genetic influences, researchers analyzed data from more than 6 million people. Their findings reveal that the 14 psychiatric disorders studied are not genetically isolated. Instead, they fall into five broad groups that share substantial genetic similarities. This clearer picture of genetic overlap could eventually help clinicians tailor care more effectively for patients with complex diagnoses.
What Genetics Can Reveal About Psychiatric Disorders
“Psychiatry is the only medical specialty with no definitive laboratory tests. We can’t give a blood test to tell whether someone has depression — we have to rely on symptoms and signs. And that’s true for almost every psychiatric disorder,” said Kendler, a world-renowned researcher for his pioneering studies in psychiatric genetics. “Genetics is a developing tool that allows us to understand the relationships between disorders. The findings from this study reflect the most comprehensive analysis of psychiatric genomic data to date and shed new light on why individuals with one psychiatric disorder often have a second or third.”
The study examined genetic material from more than 1 million people diagnosed with a childhood- or adult-onset psychiatric disorder, along with data from 5 million individuals without any diagnosed condition. By identifying genetic markers that appear more frequently in people with specific disorders, scientists can better pinpoint the biological factors that contribute to mental illness.
Shared Variants and Genetic Hot Spots
Using several complementary analytical methods, the research team explored the genetic structure of all 14 psychiatric disorders. This approach uncovered 428 genetic variants linked to more than one condition. The analysis also identified 101 areas on chromosomes that acted as “hot spots” where these shared genetic variants were especially concentrated.
Statistical modeling allowed the researchers to group the disorders based on genetic similarity. The five groups identified were:
- Compulsive disorders: obsessive-compulsive disorder, anorexia nervosa and, to a lesser extent, Tourette disorder and anxiety disorders.
- Internalizing disorders: major depression, anxiety disorders and post-traumatic stress disorder.
- Neurodevelopmental disorders: autism spectrum disorder, attention-deficit/hyperactivity disorder and, to a lesser extent, Tourette disorder.
- Schizophrenia and bipolar disorder
- Substance use disorders: opioid use disorder, cannabis use disorder, alcohol use disorder and nicotine dependence.
Which Disorders Share the Most Genetic Risk
Some conditions showed especially strong genetic connections. Major depression, anxiety and post-traumatic stress disorder shared about 90% of their genetic risk. Schizophrenia and bipolar disorder also showed substantial overlap, sharing roughly 66% of their genetic markers.
The researchers also found that disorders with shared genetic risk often followed similar biological patterns. These similarities included when shared genes were active during human development and which types of brain cells were affected. For example, genes active in oligodendrocytes, an important component of the central nervous system, were more closely linked to internalizing disorders. In contrast, genes expressed in excitatory neurons, which stimulate other neurons, were more strongly associated with schizophrenia and bipolar disorder.
Implications for Diagnosis and Treatment
According to the researchers, these results provide a strong scientific foundation for how psychiatric disorders are defined. The findings may also guide future efforts to develop new treatments or adapt existing therapies for conditions that commonly occur together.
“I feel very proud to be a part of this effort,” Kendler said. “This work really shows that we gain more for our field and for those suffering from mental illness when we come together to tackle these scientific challenges.”