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; Beate St Pourcain

doi:10.1038/s41467-024-46128-8

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, Beate St Pourcain^*

^*Corresponding author for this work

Oral Public Health

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Article number	1770
Pages (from-to)	1-15
Number of pages	15
Journal	Nature Communications
Volume	15
Early online date	27 Feb 2024
DOIs	https://doi.org/10.1038/s41467-024-46128-8
Publication status	Published - 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

The authors are grateful to all of the families in SPARK, the SPARK clinical sites and SPARK staff. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to phenotypic and genetic data on SFARI Base. This work was supported by a grant from the Simons Foundation Autism Research Initiative (SFARI ID: 514787, PI B.S.P.) covering the work of L.D.H., M.B. and M.M.J.D., in addition, to support from the Max Planck Society. F.S., E.V., S.E.F. and B.S.P. were fully supported by the Max Planck Society. C.Y.S. was supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/3). J.B. was supported by the EU-AIMS and AIMS-2-TRIALS programmes which receive support from Innovative Medicines Initiative Joint Undertaking Grant No. 115300 and 777394, the resources of which are composed of financial contributions from the European Union’s FP7 and Horizon2020 Programmes, and from the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions, and AUTISM SPEAKS, Autistica and SFARI; and by the Horizon2020 supported programme CANDY (Grant No. 847818).

Funders	Funder number
EU-AIMS
European Union’s FP7
Horizon 2020 Framework Programme
European Federation of Pharmaceutical Industries and Associations	847818
Simons Foundation Autism Research Initiative	514787
Medical Research Council
University of Bristol	MC_UU_00011/3
Max-Planck-Gesellschaft
Innovative Medicines Initiative	115300, 777394

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de Hoyos, L., Barendse, M. T., Schlag, F., van Donkelaar, M. M. J., Verhoef, E., Shapland, C. Y., Klassmann, A., Buitelaar, J., Verhulst, B., Fisher, S. E., Rai, D., & St Pourcain, B. (2024). Structural models of genome-wide covariance identify multiple common dimensions in autism. Nature Communications, 15, 1-15. Article 1770. https://doi.org/10.1038/s41467-024-46128-8

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

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