Genetic correlates of phenotypic heterogeneity in autism

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

doi:10.1038/s41588-022-01072-5

Genetic correlates of phenotypic heterogeneity in autism

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

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

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 (n_max = 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.

Original language	English
Pages (from-to)	1293-1304
Number of pages	12
Journal	Nature genetics
Volume	54
Issue number	9
DOIs	https://doi.org/10.1038/s41588-022-01072-5
Publication status	Published - Sept 2022

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10.1038/s41588-022-01072-5

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@article{1785a9b5c6d945418ae4d5f17150709c,

title = "Genetic correlates of phenotypic heterogeneity in autism",

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.",

author = "{EU-AIMS LEAP} and {iPSYCH-Autism Working Group} and {Spectrum 10K and APEX Consortia} and Varun Warrier and Xinhe Zhang and Patrick Reed and Alexandra Havdahl and Moore, {Tyler M.} and Freddy Cliquet and Leblond, {Claire S.} and Thomas Rolland and Anders Rosengren and Caceres, {Antonia San Jose} and Hannah Hayward and Daisy Crawley and Jessica Faulkner and Jessica Sabet and Claire Ellis and Bethany Oakley and Eva Loth and Tony Charman and Declan Murphy and Rosemary Holt and Jack Waldman and Jessica Upadhyay and Nicola Gunby and Lai, {Meng Chuan} and Gwilym Renouf and Amber Ruigrok and Emily Taylor and Hisham Ziauddeen and Julia Deakin and {di Bruttopilo}, {Sara Ambrosino} and {van Dijk}, Sarai and Yvonne Rijks and Tabitha Koops and Miriam Douma and Alyssia Spaan and Iris Selten and Maarten Steffers and {van Themaat}, {Anna Ver Loren} and Nico Bast and Sarah Baumeister and Larry O{\textquoteright}Dwyer and Carsten Bours and Annika Rausch and {von Rhein}, Daniel and Ineke Cornelissen and {de Bruin}, Yvette and Maartje Graauwmans and Elzbieta Kostrzewa and Elodie Cauvet and Kristiina Tammimies",

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{\textquoteright}s Horizon 2020 research and innovation program and the EFPIA and Autism Speaks, Autistica and the SFARI. V.W. is funded by St. Catharine{\textquoteright}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 Universit{\'e} de Paris Cit{\'e}. 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{\textquoteright}s Horizon 2020 research and innovation program and the EFPIA and Autism Speaks, Autistica and the SFARI. V.W. is funded by St. Catharine{\textquoteright}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 Universit{\'e} de Paris Cit{\'e}. 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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = sep,

doi = "10.1038/s41588-022-01072-5",

language = "English",

volume = "54",

pages = "1293--1304",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

TY - JOUR

T1 - Genetic correlates of phenotypic heterogeneity in autism

AU - EU-AIMS LEAP

AU - iPSYCH-Autism Working Group

AU - Spectrum 10K and APEX Consortia

AU - Warrier, Varun

AU - Zhang, Xinhe

AU - Reed, Patrick

AU - Havdahl, Alexandra

AU - Moore, Tyler M.

AU - Cliquet, Freddy

AU - Leblond, Claire S.

AU - Rolland, Thomas

AU - Rosengren, Anders

AU - Caceres, Antonia San Jose

AU - Hayward, Hannah

AU - Crawley, Daisy

AU - Faulkner, Jessica

AU - Sabet, Jessica

AU - Ellis, Claire

AU - Oakley, Bethany

AU - Loth, Eva

AU - Charman, Tony

AU - Murphy, Declan

AU - Holt, Rosemary

AU - Waldman, Jack

AU - Upadhyay, Jessica

AU - Gunby, Nicola

AU - Lai, Meng Chuan

AU - Renouf, Gwilym

AU - Ruigrok, Amber

AU - Taylor, Emily

AU - Ziauddeen, Hisham

AU - Deakin, Julia

AU - di Bruttopilo, Sara Ambrosino

AU - van Dijk, Sarai

AU - Rijks, Yvonne

AU - Koops, Tabitha

AU - Douma, Miriam

AU - Spaan, Alyssia

AU - Selten, Iris

AU - Steffers, Maarten

AU - van Themaat, Anna Ver Loren

AU - Bast, Nico

AU - Baumeister, Sarah

AU - O’Dwyer, Larry

AU - Bours, Carsten

AU - Rausch, Annika

AU - von Rhein, Daniel

AU - Cornelissen, Ineke

AU - de Bruin, Yvette

AU - Graauwmans, Maartje

AU - Kostrzewa, Elzbieta

AU - Cauvet, Elodie

AU - Tammimies, Kristiina

N1 - 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).

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85133877615&partnerID=8YFLogxK

U2 - 10.1038/s41588-022-01072-5

DO - 10.1038/s41588-022-01072-5

M3 - Article

C2 - 35654973

AN - SCOPUS:85133877615

SN - 1061-4036

VL - 54

SP - 1293

EP - 1304

JO - Nature genetics

JF - Nature genetics

IS - 9

ER -

Genetic correlates of phenotypic heterogeneity in autism

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