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Modeling Study Reveals Genetic Architecture Across Psychiatric Conditions

NEW YORK – A team from VU Amsterdam, the University of Texas at Austin, and elsewhere has started untangling the complex genetic architecture of nearly a dozen major psychiatric conditions, ranging from attention deficit hyperactivity disorder (ADHD), problematic alcohol use, and post-traumatic stress disorder to schizophrenia and Tourette syndrome.

"Collectively, these results offer key insights into the shared and disorder-specific mechanisms of genetic risk for psychiatric disease," first and corresponding author Andrew Grotzinger, a researcher at the University of Colorado at Boulder, and his colleagues wrote.

As they reported in Nature Genetics on Thursday, the researchers used a stratified genomic structural equation modeling (SEM) approach to characterize the genetic architecture of 11 major psychiatric conditions, relying on data from prior genome-wide association studies. They also incorporated functional genomic results, dozens of biological or behavioral clues, circadian activity measurements, and more than 100 brain morphology metrics.

"Our results offer critical insights into shared and disorder-specific mechanisms of genetic risk and suggest possible avenues for revising a psychiatric nosology currently defined largely by clinical observation," the authors explained. "Evidence derived from multivariate genetic analysis, alongside evidence at other levels of explanation (for example, cognitive neuroscience, environmental stressors) could guide the development of new treatments and revision of established diagnostic taxonomies."

With SEM and a correlated factors modeling approach, the team narrowed in on the collections of genes that appeared to have an outsized impact on the four factors identified, which were classified as neurodevelopmental, compulsive, psychotic, or internalizing factors.

"We used genomic SEM to identify four broad factors … that provide a reasonable model of the genetic correlations among 11 major psychiatric disorders," the authors reported. "We find that the compulsive, psychotic, and internalizing factors are generally effective at describing the genetic relationships among psychiatric disorders at biobehavioral, functional genomic, and molecular levels of analysis."

For example, the researchers noted that the psychiatric conditions in the psychotic features group tended to show ties to predicted protein-truncating mutations in genes that are typically considered mutation-intolerant, particularly those known for being expressed in excitatory brain cells or "GABAergic" brain cells that produce or are influenced by the gamma-aminobutyric acid (GABA) neurotransmitter.

With its multivariate association approach, the team flagged 152 independent genetic loci linked to the psychiatric factors identified, including 20 loci not found in the past. Another nine sites in the genome had heterogeneous ties across psychiatric conditions from the four factor groups.

More generally, the authors noted that although genetic correlations typically range from intermediate to high for the psychiatric conditions considered, "we find little utility of a single dimension of genetic risk across psychiatric disorders either at the level of biobehavioral correlates or at the level of individual variants."