Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder

Sonja LaBianca, Isabell Brikell, Dorte Helenius, Robert Loughnan, Joel Mefford, Clare E. Palmer, Rebecca Walker, Jesper R. Gådin, Morten Krebs, Vivek Appadurai, Morteza Vaez, Esben Agerbo, Marianne Giørtz Pedersen, Anders D. Børglum, David M. Hougaard, Ole Mors, Merete Nordentoft, Preben Bo Mortensen, Kenneth S. Kendler, Terry L. JerniganDaniel H. Geschwind, Andrés Ingason, Andrew W. Dahl, Noah Zaitlen, Søren Dalsgaard, Thomas M. Werge*, Andrew J. Schork

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstract

Attention deficit hyperactivity disorder (ADHD) is a complex disorder that manifests variability in long-term outcomes and clinical presentations. The genetic contributions to such heterogeneity are not well understood. Here we show several genetic links to clinical heterogeneity in ADHD in a case-only study of 14,084 diagnosed individuals. First, we identify one genome-wide significant locus by comparing cases with ADHD and autism spectrum disorder (ASD) to cases with ADHD but not ASD. Second, we show that cases with ASD and ADHD, substance use disorder and ADHD, or first diagnosed with ADHD in adulthood have unique polygenic score (PGS) profiles that distinguish them from complementary case subgroups and controls. Finally, a PGS for an ASD diagnosis in ADHD cases predicted cognitive performance in an independent developmental cohort. Our approach uncovered evidence of genetic heterogeneity in ADHD, helping us to understand its etiology and providing a model for studies of other disorders.
OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind56
Udgave nummer2
Sider (fra-til)234-244
Antal sider11
ISSN1061-4036
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
Data used in the preparation of this article were obtained from the ABCD study ( https://abcdstudy.org ), held by the National Institute of Mental Health (NIMH) Data Archive. This is a multisite longitudinal study designed to recruit more than 10,000 children aged 9–10 years and follow them over 10 years into early adulthood. The ABCD study is supported by the National Institutes of Health (NIH) and additional federal partners under award nos. U01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123 and U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html . A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/principal-investigators.html . ABCD Consortium investigators designed and implemented the study or provided data but did not necessarily participate in the analysis or the writing of this article. This article reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD Consortium investigators. The ABCD data repository grows and changes over time. The iPSYCH initiative is funded by the Lundbeck Foundation (grant nos. R102-A9118 and R155-2014-1724), the Mental Health Services Capital Region of Denmark, the University of Copenhagen, Aarhus University and the University Hospital in Aarhus. Genotyping of iPSYCH samples was supported by grants from the Lundbeck Foundation, the Stanley Foundation, the Simons Foundation (SFARI 311789) and the NIMH (5U01MH094432-02). The IPSYCH initiative uses the Danish National Biobank resource, which is supported by the Novo Nordisk Foundation. IPSYCH data were stored and analyzed at the Computerome HPC facility ( http://www.computerome.dtu.dk/ ); we are grateful for continuous support from the HPC team led by A. Syed of DTU Bioinformatics, Technical University of Denmark. We acknowledge funding from the Lundbeck Foundation under fellowship no. R335-2019-2318 (A.J.S.), the National Institute for Aging of the NIH under award nos. U19AG023122, U24AG051129S1, UH2AG064706 and UH2AG064706S1 (A.J.S.), the Research Fund of the Mental Health Services – Capital Region of Denmark R4A92 (S.L.), the Lundbeck Foundation R208-2015-3951 (S.L.), Fonden for Faglig Udvikling af Speciallægepraksis (The Foundation for the Professional Development of Specialist Medical Practice) 38850/16 (S.L.), a European Commission Horizon 2020 grant no. 667302 (S.D.), Helsefonden (Health Fund) grant no. 19-8-0260 (S.D.) and the European Union’s Horizon 2020 research and innovation program under grant no. 847879 (S.D.).

Funding Information:
Data used in the preparation of this article were obtained from the ABCD study (https://abcdstudy.org), held by the National Institute of Mental Health (NIMH) Data Archive. This is a multisite longitudinal study designed to recruit more than 10,000 children aged 9–10 years and follow them over 10 years into early adulthood. The ABCD study is supported by the National Institutes of Health (NIH) and additional federal partners under award nos. U01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123 and U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/principal-investigators.html. ABCD Consortium investigators designed and implemented the study or provided data but did not necessarily participate in the analysis or the writing of this article. This article reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD Consortium investigators. The ABCD data repository grows and changes over time. The iPSYCH initiative is funded by the Lundbeck Foundation (grant nos. R102-A9118 and R155-2014-1724), the Mental Health Services Capital Region of Denmark, the University of Copenhagen, Aarhus University and the University Hospital in Aarhus. Genotyping of iPSYCH samples was supported by grants from the Lundbeck Foundation, the Stanley Foundation, the Simons Foundation (SFARI 311789) and the NIMH (5U01MH094432-02). The IPSYCH initiative uses the Danish National Biobank resource, which is supported by the Novo Nordisk Foundation. IPSYCH data were stored and analyzed at the Computerome HPC facility (http://www.computerome.dtu.dk/); we are grateful for continuous support from the HPC team led by A. Syed of DTU Bioinformatics, Technical University of Denmark. We acknowledge funding from the Lundbeck Foundation under fellowship no. R335-2019-2318 (A.J.S.), the National Institute for Aging of the NIH under award nos. U19AG023122, U24AG051129S1, UH2AG064706 and UH2AG064706S1 (A.J.S.), the Research Fund of the Mental Health Services – Capital Region of Denmark R4A92 (S.L.), the Lundbeck Foundation R208-2015-3951 (S.L.), Fonden for Faglig Udvikling af Speciallægepraksis (The Foundation for the Professional Development of Specialist Medical Practice) 38850/16 (S.L.), a European Commission Horizon 2020 grant no. 667302 (S.D.), Helsefonden (Health Fund) grant no. 19-8-0260 (S.D.) and the European Union’s Horizon 2020 research and innovation program under grant no. 847879 (S.D.).

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2023.

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