Novel tools for comparing the architecture of psychopathology between neurogenetic disorders: An application to X- vs. Y-chromosome aneuploidy effects in males.

Background: Psychiatric symptoms are typically highly inter-correlated at the group level. Collectively, these correlations define the architecture of psychopathology-informing taxonomic and mechanistic models in psychiatry. However, to date, it remains unclear if this architecture differs between etiologically distinct subgroups, despite the core relevance of this understanding for personalized medicine. Here, we introduce a new analytic pipeline to probe group differences in the psychopathology architecture-demonstrated through comparison of two distinct neurogenetic disorders. Methods: We use a large questionnaire battery in 300 individuals aged 5-25 years ( Results: Behavior correlation matrices describe the architecture of psychopathology in each syndrome. Comparison of matrix row averages reveals that autism-related features and externalizing symptoms are most differentially coupled to other aspects of psychopathology in XXY/KS vs. XYY. Clustering the difference between matrices captures coordinated group differences in pairwise coupling between measures of psychopathology: XXY/KS increases coherence among externalizing, internalizing, and autism-related features, while XYY syndrome shows greater coherence in dissociality and early neurodevelopmental impairment. Conclusions: These methods offer new insights into X- and Y-chromosome dosage effects on behavior, and our shared code can now be applied to other clinical groups of interest-helping to hone mechanistic models and inform the tailoring of care.