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Genetic correlates of phenotypic heterogeneity in autism

Research output: Contribution to journalArticlepeer-review

EU-AIMS LEAP, iPSYCH-Autism Working Group, Spectrum 10K and APEX Consortia

Original languageEnglish
Pages (from-to)1293-1304
Number of pages12
JournalNature genetics
Volume54
Issue number9
DOIs
Accepted/In press2022
PublishedSep 2022

Bibliographical note

Funding Information: S.B.-C. received funding from the Wellcome Trust (214322\Z\18\Z). For the purpose of open access, we have applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. S.B.-C. also received funding from the Autism Centre of Excellence, the SFARI, the Templeton World Charitable Fund, the MRC and the National Institute for Health Research Cambridge Biomedical Research Centre. The research was supported by the National Institute for Health Research Applied Research Collaboration East of England. Any views expressed are those of the author(s) and not necessarily those of the funder. Some of 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 program and the EFPIA and Autism Speaks, Autistica and the SFARI. V.W. is funded by St. Catharine’s College, Cambridge. T.B. has received funding from the Institut Pasteur, the CNRS, the Bettencourt–Schueller and the Cognacq–Jay Foundations, the APHP and the Université de Paris Cité. We acknowledge with gratitude the generous support of D. and M. Gillings in strengthening the collaboration between S.B.-C. and T.B. and between Cambridge University and the Institut Pasteur. The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the NIMH (1U01MH109514-01 to A.D.B.) and the universities and university hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). We thank J. Sebat for sharing the de novo variant calls in the SPARK and SSC datasets. We are grateful to all families at the participating 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 and E. Wijsman). We are grateful to all families in the SPARK study, the SPARK clinical sites and SPARK staff. Funding Information: S.B.-C. received funding from the Wellcome Trust (214322\Z\18\Z). For the purpose of open access, we have applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. S.B.-C. also received funding from the Autism Centre of Excellence, the SFARI, the Templeton World Charitable Fund, the MRC and the National Institute for Health Research Cambridge Biomedical Research Centre. The research was supported by the National Institute for Health Research Applied Research Collaboration East of England. Any views expressed are those of the author(s) and not necessarily those of the funder. Some of 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 program and the EFPIA and Autism Speaks, Autistica and the SFARI. V.W. is funded by St. Catharine’s College, Cambridge. T.B. has received funding from the Institut Pasteur, the CNRS, the Bettencourt–Schueller and the Cognacq–Jay Foundations, the APHP and the Université de Paris Cité. We acknowledge with gratitude the generous support of D. and M. Gillings in strengthening the collaboration between S.B.-C. and T.B. and between Cambridge University and the Institut Pasteur. The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the NIMH (1U01MH109514-01 to A.D.B.) and the universities and university hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). We thank J. Sebat for sharing the de novo variant calls in the SPARK and SSC datasets. We are grateful to all families at the participating 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 and E. Wijsman). We are grateful to all families in the SPARK study, the SPARK clinical sites and SPARK staff. Publisher Copyright: © 2022, The Author(s).

King's Authors

Abstract

The substantial phenotypic heterogeneity in autism limits our understanding of its genetic etiology. To address this gap, here we investigated genetic differences between autistic individuals (nmax = 12,893) based on core and associated features of autism, co-occurring developmental disabilities and sex. We conducted a comprehensive factor analysis of core autism features in autistic individuals and identified six factors. Common genetic variants were associated with the core factors, but de novo variants were not. We found that higher autism polygenic scores (PGS) were associated with lower likelihood of co-occurring developmental disabilities in autistic individuals. Furthermore, in autistic individuals without co-occurring intellectual disability (ID), autism PGS are overinherited by autistic females compared to males. Finally, we observed higher SNP heritability for autistic males and for autistic individuals without ID. Deeper phenotypic characterization will be critical in determining how the complex underlying genetics shape cognition, behavior and co-occurring conditions in autism.

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