Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups

Manuel Mattheisen; Jakob Grove; Thomas D. Als; Joanna Martin; Georgios Voloudakis; Sandra Meier; Ditte Demontis; Jaroslav Bendl; Raymond Walters; Caitlin E. Carey; Anders Rosengren; Nora I. Strom; Mads Engel Hauberg; Biao Zeng; Gabriel Hoffman; Wen Zhang; Jonas Bybjerg-Grauholm; Marie Bækvad-Hansen; Esben Agerbo; Bru Cormand; Merete Nordentoft; Thomas Werge; Ole Mors; David M. Hougaard; Joseph D. Buxbaum; Stephen V. Faraone; Barbara Franke; Søren Dalsgaard; Preben B. Mortensen; Elise B. Robinson; Panos Roussos; Benjamin M. Neale; Mark J. Daly; Anders D. Børglum

doi:10.1038/s41588-022-01171-3

Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups

Manuel Mattheisen
, Jakob Grove
, Thomas D. Als
, Joanna Martin
, Georgios Voloudakis
, Sandra Meier
, Ditte Demontis
, Jaroslav Bendl
, Raymond Walters
, Caitlin E. Carey
, Anders Rosengren
, Nora I. Strom
, Mads Engel Hauberg
, Biao Zeng
, Gabriel Hoffman
, Wen Zhang
, Jonas Bybjerg-Grauholm
, Marie Bækvad-Hansen
, Esben Agerbo
, Bru Cormand

Merete Nordentoft, Thomas Werge, Ole Mors, David M. Hougaard, Joseph D. Buxbaum, Stephen V. Faraone, Barbara Franke, Søren Dalsgaard, Preben B. Mortensen, Elise B. Robinson, Panos Roussos, Benjamin M. Neale, Mark J. Daly, Anders D. Børglum

Psychiatry

Upstate Medical University

Aarhus University
Dalhousie University
Ludwig Maximilian University of Munich
iPSYCH
Center for Genomics and Personalized Medicine
Cardiff University
Icahn School of Medicine at Mount Sinai
Harvard University
Broad Institute
University of Copenhagen
Karolinska Institutet
Statens Serum Institut
University of Barcelona
Center for Biological Research and Center for Biomedical Network Research on Rare Diseases
Institut de Recerca Sant Joan de Déu (IR-SJD)
Mental Health Centre Copenhagen
University Hospital
Radboud University Nijmegen
VA Medical Center
University of Helsinki

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

53 Scopus citations

Abstract

Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.

Original language	English
Pages (from-to)	1470-1478
Number of pages	9
Journal	Nature Genetics
Volume	54
Issue number	10
DOIs	https://doi.org/10.1038/s41588-022-01171-3
State	Published - Oct 2022

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Mattheisen, M., Grove, J., Als, T. D., Martin, J., Voloudakis, G., Meier, S., Demontis, D., Bendl, J., Walters, R., Carey, C. E., Rosengren, A., Strom, N. I., Hauberg, M. E., Zeng, B., Hoffman, G., Zhang, W., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Agerbo, E., ... Børglum, A. D. (2022). Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups. Nature Genetics, 54(10), 1470-1478. https://doi.org/10.1038/s41588-022-01171-3

@article{470b67960f414cff8d1674b5988327b7,

title = "Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups",

abstract = "Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.",

author = "Manuel Mattheisen and Jakob Grove and Als, \{Thomas D.\} and Joanna Martin and Georgios Voloudakis and Sandra Meier and Ditte Demontis and Jaroslav Bendl and Raymond Walters and Carey, \{Caitlin E.\} and Anders Rosengren and Strom, \{Nora I.\} and Hauberg, \{Mads Engel\} and Biao Zeng and Gabriel Hoffman and Wen Zhang and Jonas Bybjerg-Grauholm and Marie B{\ae}kvad-Hansen and Esben Agerbo and Bru Cormand and Merete Nordentoft and Thomas Werge and Ole Mors and Hougaard, \{David M.\} and Buxbaum, \{Joseph D.\} and Faraone, \{Stephen V.\} and Barbara Franke and S{\o}ren Dalsgaard and Mortensen, \{Preben B.\} and Robinson, \{Elise B.\} and Panos Roussos and Neale, \{Benjamin M.\} and Daly, \{Mark J.\} and B{\o}rglum, \{Anders D.\}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = oct,

doi = "10.1038/s41588-022-01171-3",

language = "English",

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Mattheisen, M, Grove, J, Als, TD, Martin, J, Voloudakis, G, Meier, S, Demontis, D, Bendl, J, Walters, R, Carey, CE, Rosengren, A, Strom, NI, Hauberg, ME, Zeng, B, Hoffman, G, Zhang, W, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Agerbo, E, Cormand, B, Nordentoft, M, Werge, T, Mors, O, Hougaard, DM, Buxbaum, JD, Faraone, SV, Franke, B, Dalsgaard, S, Mortensen, PB, Robinson, EB, Roussos, P, Neale, BM, Daly, MJ & Børglum, AD 2022, 'Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups', Nature Genetics, vol. 54, no. 10, pp. 1470-1478. https://doi.org/10.1038/s41588-022-01171-3

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T1 - Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups

AU - Mattheisen, Manuel

AU - Grove, Jakob

AU - Als, Thomas D.

AU - Martin, Joanna

AU - Voloudakis, Georgios

AU - Meier, Sandra

AU - Demontis, Ditte

AU - Bendl, Jaroslav

AU - Walters, Raymond

AU - Carey, Caitlin E.

AU - Rosengren, Anders

AU - Strom, Nora I.

AU - Hauberg, Mads Engel

AU - Zeng, Biao

AU - Hoffman, Gabriel

AU - Zhang, Wen

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-Hansen, Marie

AU - Agerbo, Esben

AU - Cormand, Bru

AU - Nordentoft, Merete

AU - Werge, Thomas

AU - Mors, Ole

AU - Hougaard, David M.

AU - Buxbaum, Joseph D.

AU - Faraone, Stephen V.

AU - Franke, Barbara

AU - Dalsgaard, Søren

AU - Mortensen, Preben B.

AU - Robinson, Elise B.

AU - Roussos, Panos

AU - Neale, Benjamin M.

AU - Daly, Mark J.

AU - Børglum, Anders D.

PY - 2022/10

Y1 - 2022/10

N2 - Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.

AB - Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.

UR - https://www.scopus.com/pages/publications/85138743007

U2 - 10.1038/s41588-022-01171-3

DO - 10.1038/s41588-022-01171-3

M3 - Article

C2 - 36163277

SN - 1061-4036

VL - 54

SP - 1470

EP - 1478

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups

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