Structural models of genome-wide covariance identify multiple common dimensions in autism

Lucía de Hoyos, Maria T. Barendse, Fenja Schlag, Marjolein M. J. van Donkelaar, Ellen Verhoef, Chin Yang Shapland, Alexander Klassmann, Jan Buitelaar, Brad Verhulst, Simon E. Fisher, Dheeraj Rai and Beate St Pourcain ()
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Lucía de Hoyos: Max Planck Institute for Psycholinguistics
Maria T. Barendse: Max Planck Institute for Psycholinguistics
Fenja Schlag: Max Planck Institute for Psycholinguistics
Marjolein M. J. van Donkelaar: Max Planck Institute for Psycholinguistics
Ellen Verhoef: Max Planck Institute for Psycholinguistics
Chin Yang Shapland: MRC Integrative Epidemiology Unit, University of Bristol
Alexander Klassmann: University of Cologne
Jan Buitelaar: Cognition and Behaviour, Radboud University
Brad Verhulst: Texas A&M University
Simon E. Fisher: Max Planck Institute for Psycholinguistics
Dheeraj Rai: University of Bristol
Beate St Pourcain: Max Planck Institute for Psycholinguistics

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Common genetic variation has been associated with multiple phenotypic features in Autism Spectrum Disorder (ASD). However, our knowledge of shared genetic factor structures contributing to this highly heterogeneous phenotypic spectrum is limited. Here, we developed and implemented a structural equation modelling framework to directly model genomic covariance across core and non-core ASD phenotypes, studying autistic individuals of European descent with a case-only design. We identified three independent genetic factors most strongly linked to language performance, behaviour and developmental motor delay, respectively, studying an autism community sample (N = 5331). The three-factorial structure was largely confirmed in independent ASD-simplex families (N = 1946), although we uncovered, in addition, simplex-specific genetic overlap between behaviour and language phenotypes. Multivariate models across cohorts revealed novel associations, including links between language and early mastering of self-feeding. Thus, the common genetic architecture in ASD is multi-dimensional with overarching genetic factors contributing, in combination with ascertainment-specific patterns, to phenotypic heterogeneity.

Date: 2024
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DOI: 10.1038/s41467-024-46128-8

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