Researchers have uncovered shared genetic pathways that link multiple psychiatric disorders. These new findings have the potential to change the way psychiatric disorders are diagnosed and treated, especially for patients with multiple mental health illnesses.

The large genomic analysis that included more than 1 million individuals revealed “pervasive” genetic overlap, involving 238 genetic variants across 14 childhood- and adult-onset psychiatric 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,” co-corresponding author Andrew Grotzinger, PhD, assistant professor of psychology and neuroscience at the University of Colorado Boulder, said in a statement. 

“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,” Grotzinger said.

The study was published online on December 10 in Nature.

Challenging Diagnostic Boundaries 

Many psychiatric disorders overlap clinically and genetically, complicating efforts to draw clear diagnostic lines. This is especially true for schizophrenia and bipolar disorder, which have long been considered distinct illnesses but are now shown by genomic research to share much of their underlying genetic risk.

Recent cross-disorder analyses have identified hundreds of genetic variants that influence multiple conditions, but it’s still unclear how much genetic risk is shared and how much is specific to each disorder.

To address this gap, researchers examined DNA data from more than 1 million individuals diagnosed with psychiatric disorders and 5 million individuals without a psychiatric diagnosis.

Using genetic association data and multiple statistical approaches, they found that 14 childhood- and adult-onset psychiatric disorders cluster into five categories based on a high level of shared genetic similarities. These include:

• Compulsive disorders: Obsessive-compulsive disorder, anorexia nervosa, and, to a lesser extent, Tourette disorder, and anxiety disorders
• Internalizing disorders: Major depression, anxiety disorders, and posttraumatic 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

The close genetic overlap between schizophrenia and bipolar disorder was notable, the researchers said, given that these two disorders have historically been viewed as distinct.

“Genetically, we saw that they are more similar than they are unique,” Grotzinger said in the release. 

The researchers also uncovered specific biological pathways that may underlie individual groupings. They found that shared genetic risk across disorders was enriched for broad processes, such as gene regulation early in brain development, while specific groups showed distinct cellular signatures.

For example, genes linked to schizophrenia and bipolar disorder were strongly enriched in excitatory neurons, whereas internalizing disorders such as depression and anxiety were more closely tied to nonneuronal oligodendrocytes, specialized cells involved in maintaining brain connectivity.

Immediate Clinical Implications?

Clinically, the results suggest that current symptom-based diagnostic categories may not reflect underlying biology and that future classification systems could benefit from incorporating genetic architecture.

The observation that “few genetic variants are unique to a single diagnosis” suggests that categories in the Diagnostic and Statistical Manual of Mental Disorders (DSM) “might be useful clinically but are seemingly arbitrary at a biological level,” Abdel Abdellaoui, PhD, with the Department of Psychiatry, University of Amsterdam, Amsterdam, Netherlands, wrote a linked editorial. Jordan Smoller, MD, co-corresponding author on the paper, agreed.

“Our current diagnostic system, as reflected in the DSM, is largely based on descriptive syndromes defined by expert consensus. That approach has been clinically useful, but it also has limitations — particularly when patients meet criteria for multiple disorders or move between diagnoses over time,” Smoller, who directs the Center for Precision Psychiatry at Mass General Brigham in Boston, told Medscape Medical News.

“By identifying genetic risk factors that are shared across conditions, this work helps point toward underlying biological dimensions of vulnerability that cut across traditional categories. Over time, that could support efforts to move beyond a purely descriptive classification system toward one that is more closely aligned with causes and mechanisms of illness,” Smoller said.

“For clinicians, this doesn’t mean abandoning diagnosis but rather recognizing that diagnostic labels may capture different expressions of shared risk, with important implications for how we conceptualize illness, track risk over time, and think about treatment strategies that target common underlying pathways,” Smoller added. 

He cautioned that in the near term, these findings are not sufficient to guide genetic testing, diagnosis, or prescribing decisions, and they are not intended to change clinical practice directly. However, they do reinforce several perspectives that are already familiar to clinicians.

“The results help explain why comorbidity is the rule rather than the exception in psychiatry, and why patients often receive multiple diagnoses over time without a clear boundary between disorders,” Smoller told Medscape Medical News.

“They also provide a biological rationale for the use of treatments that show benefit across diagnostic categories, including medications and psychotherapies with transdiagnostic effects,” Smoller noted.

“More broadly, the findings support a dimensional view of psychiatric risk and symptom expression, which aligns with how many clinicians already assess severity, impairment, and treatment response in real-world practice,” he added.

Next Steps to Clinical Translation

Yet, Smoller cautioned that several steps are needed before the findings can be translated into clinical tools or guidelines.

First, the results need to be replicated and extended across more diverse ancestry groups, since most large genetic studies to date have been conducted primarily in individuals of European ancestry, he explained.

Second, the shared genetic factors identified must be linked more directly to clinically meaningful outcomes, such as illness course, treatment response, and functional recovery, rather than diagnosis alone, he said.

“Equally important is integrating these genetic insights with other levels of information — including environmental exposures, developmental timing, neurobiology, and clinical phenotypes — to better understand when shared risk pathways matter most,” Smoller said.

From a translational perspective, the identification of biological pathways and cell types associated with shared risk across disorders also points to potential targets for therapeutic development, particularly for conditions that commonly co-occur and are currently treated separately.

Realizing that potential will require experimental validation and careful testing to determine whether targeting these pathways leads to meaningful clinical benefit,” Smoller added.

This work was supported by grants from governmental and charitable bodies, as well as philanthropic donations. A complete list of author disclosures is available with the original article. Abdellaoui reported no disclosures.