Identifying rare genetic variants in 21 highly multiplex autism families: the role of diagnosis and autistic traits.

Autism is a highly heritable, heterogeneous, neurodevelopmental condition. Large-scale genetic studies, predominantly focussing on simplex families and clinical diagnoses of autism have identified hundreds of genes associated with autism. Yet, the contribution of these classes of genes to multiplex families and autistic traits still warrants investigation. Here, we conducted whole-genome sequencing of 21 highly multiplex autism families, with at least three autistic individuals in each family, to prioritise genes associated with autism. Using a combination of both autistic traits and clinical diagnosis of autism, we identify rare variants in genes associated with autism, and related neurodevelopmental conditions in multiple families. We identify a modest excess of these variants in autistic individuals compared to individuals without an autism diagnosis. Finally, we identify a convergence of the genes identified in molecular pathways related to development and neurogenesis. In sum, our analysis provides initial evidence to demonstrate the value of integrating autism diagnosis and autistic traits to prioritise genes.

Description

Acknowledgements: This study was funded by the Templeton World Charitable Foundation, Inc. to whom we are grateful for their generous support. In addition, SB-C received funding from the Wellcome Trust 214322\Z\18\Z. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The results leading to this publication have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme, EFPIA, AUTISM SPEAKS, Autistica, and SFARI. SB-C also received funding from the Autism Centre of Excellence, SFARI, the MRC, and the NIHR Cambridge Biomedical Research Centre. The research was supported by the National Institute for Health Research (NIHR) Applied Research Collaboration East of England and funding for the Gurdon Institute (Wellcome Trust Core Grant (203144/Z/16/Z)). Any views expressed are those of the author(s) and not necessarily those of the funder. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. We deeply thank the families who participated in this study.

Funder: Templeton World Charity Foundation (Templeton World Charity Foundation, Inc.); doi: https://doi.org/10.13039/501100011730

Keywords

Humans, Autistic Disorder, Neurodevelopmental Disorders, Phenotype, Autism Spectrum Disorder

Journal Title

Mol Psychiatry

Journal ISSN

1359-4184
1476-5578

Volume Title

28

Publisher

Springer Nature

Publisher DOI

https://doi.org/10.1038/s41380-022-01938-4

Rights and licensing

Except where otherwised noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/

Sponsorship

Wellcome Trust (203144/Z/16/Z)
Wellcome Trust (214322/Z/18/Z)
Wellcome Trust (203144/A/16/Z)

This study was funded by the Templeton World Charitable Foundation, Inc. to whom we are grateful for their generous support. In addition, SBC received funding from the Wellcome Trust 214322\Z\18\Z. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The results leading to this publication have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2- TRIALS. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme, EFPIA, AUTISM SPEAKS, Autistica, and SFARI. SBC also received funding from the Autism Centre of Excellence, SFARI, the MRC, and the NIHR Cambridge Biomedical Research Centre. The research was supported by the National Institute for Health Research (NIHR) Applied Research Collaboration East of England. Any views expressed are those of the author(s) and not necessarily those of the funder. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Any views expressed are those of the author(s) and not necessarily those of the funders (IHI-JU2).

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