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 (n = 102 XXY/KS, n = 64 XYY, n = 134 age-matched XY) to characterize the structure of correlations among 53 diverse measures of psychopathology in XXY/KS and XYY syndrome—enabling us to compare the effects of X- vs. Y-chromosome dosage on the architecture of psychopathology at multiple, distinctly informative levels. 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.

The authors have declared no competing interest.

This study was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH) (NIH Annual Report Number: ZIAMH002949; Protocol: 89-M0006; ClinicalTrials.gov Number: NCT00001246).

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This research was approved by the National Institute of Mental Health (NIMH) Institutional Review Board (ClinicalTrials.gov Number: NCT00001246).

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The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.