A new peer-reviewed study published in Genomic Psychiatry has provided quantitative insight into how genetic risks for psychiatric disorders overlap and differ across diagnoses. The research, led by Dr. Kenneth S. Kendler of Virginia Commonwealth University, analyzed data from more than two million individuals born in Sweden between 1950 and 1995 to measure "genetic specificity"—the proportion of genetic risk unique to a particular disorder compared to the risk shared with other psychiatric conditions.
The team, which included Dr. Henrik Ohlsson, Dr. Jan Sundquist, and Dr. Kristina Sundquist from Lund University, focused on nine major psychiatric and substance use disorders: schizophrenia, bipolar disorder, alcohol use disorder, ADHD, autism spectrum disorder, PTSD, major depression, anxiety disorder, and drug use disorder. Using family genetic risk scores based on morbidity patterns among relatives up to fifth degree and adjusting for cohabitation effects, they determined how much of the genetic vulnerability was specific to each diagnosis.
Schizophrenia had the highest genetic specificity at 73.1%, indicating that nearly three-quarters of its genetic liability is unique to the condition. Bipolar disorder followed at 54.8%, with alcohol use disorder close behind at 54.1%. Disorders such as ADHD (48.2%), autism spectrum disorder (47.5%), and PTSD (47.4%) formed a middle tier.
Major depression (41.1%), anxiety disorder (38.6%), and drug use disorder (29.5%) showed lower specificity values—meaning much of their genetic risk overlaps with other psychiatric conditions rather than being exclusive.
"What surprised us was the sheer range," said Dr. Kenneth S. Kendler.
The findings also revealed that genetic specificity is not fixed but varies depending on clinical features like age at onset, recurrence frequency, and treatment setting.
For example, early-onset bipolar cases had higher specificity than late-onset cases; those with multiple recurrences were more genetically specific than those with fewer episodes; and patients treated in hospitals showed higher specificity compared to those managed only in primary care settings—a difference exceeding 30 percentage points for bipolar disorder.
PTSD demonstrated an opposite trend: later onset cases had higher specificity than earlier ones; individuals treated exclusively in primary care exhibited greater specificity than hospitalized patients.
"Genetic specificity is not some abstract property locked inside the genome," Dr. Kendler explained. "It moves. It responds to clinical features that every psychiatrist can observe at the bedside. A hospitalized bipolar patient and one seen only in primary care carry substantially different levels of genetic specificity.."
Hospitalized depression cases were found to be less genetically specific than those treated outside hospitals—a distinction attributed by researchers to hospitalizations often being triggered by behaviors linked with elevated risks for externalizing disorders such as ADHD or substance abuse rather than mood pathology alone.
Sensitivity analyses indicated these findings are robust even after accounting for comorbidities or sex differences; men displayed higher specificities for alcohol use and drug use disorders compared to women.
A leave-one-out analysis confirmed that removing any single comparator generally did not affect results significantly except among pairs known for high shared genetics: major depression/anxiety disorder and alcohol/drug use disorders.
The results are consistent with recent molecular studies using polygenic risk scores that identified both broad general psychopathology factors ("P-factor")—which accounted for most variance among internalizing disorders—and more distinct subfactors like schizophrenia-bipolar groups sharing less variance with this general factor.
While Swedish registry data ensures large sample sizes covering all affected individuals nationally over decades—with diagnostic quality supported by validation studies—the authors note limitations regarding potential differences if replicated outside Scandinavia or among populations with differing healthcare systems or ethnic backgrounds.
Comorbidity plays a key role: highly heritable but less comorbid conditions like schizophrenia show high specificity while common but frequently comorbid illnesses like depression have low specificity—a pattern borne out in this study’s results.
Dr. Kendler reflected on the broader implications: "We have been debating whether psychiatric disorders are truly distinct since the 1800s," he said."Now we can actually put numbers on it.Some of our diagnostic categories carve nature much more cleanly at the genetic joints than others,and clinicians and researchers alike need to reckon with that."
This comprehensive investigation demonstrates how integrating population-based registry data with advanced analytic methods can clarify fundamental questions about mental illness classification while suggesting practical applications in research design and clinical decision-making.
