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

Nature Genetics volume 56, pages 234–244 (2024)Cite this article

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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.

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Fig. 1: ADHD-adjacent traits are associated with genetic variability among diagnosed individuals.
Fig. 2: rs8178395 is specifically associated with an ADHD-adjacent ASD diagnosis.
Fig. 3: ADHD-adjacent traits share polygenes with psychiatric, cognitive and sociobehavioral traits.
Fig. 4: Profiles of PGS for psychiatric, cognitive and sociobehavioral traits define aspects of heterogeneity in ADHD.
Fig. 5: Polygenes for ADHD-adjacent ASD are associated with cognitive performance in an independent, typically developing cohort.

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Data availability

The consent structure of iPSYCH and Danish law prevent individual genotype and phenotype data from being shared publicly. Reasonable requests to access individual-level data to verify the findings in this article can be accommodated with permission from the Danish Scientific Ethics Committee, the Danish Health Data Authority, the Danish Data Protection Agency and the Danish Neonatal Screening Biobank Steering Committee; interested parties can contract T.M.W. and expect a response within 1 week. Approvals for access can take several months and are governed by strict data use agreements. The ABCD study data can be accessed, by request, from the NIMH Data Archive (https://nda.nih.gov/abcd). The GWAS summary statistics used in this work were downloaded from and are available in public repositories as described in Supplementary Table 28. Leave-one-study-out meta-analysis summary statistics for psychiatric disorders are available upon request from the Psychiatric Genomics Consortium Disorder Working Group chairs (https://pgc.unc.edu/for-researchers/data-access-committee/data-access-information/). The eQTL and sQTL visualizations and the data used for the analyses described in this article were obtained from the GTEx portal (https://gtexportal.org/) on 10 March 2021 and 23 October 2023.

Code availability

The code for the multinomial regression tests and supplementary simulations is available at https://github.com/AndrewSchork/. Other software used for the analyses are publicly available as described in the Methods and Reporting Summary. The wrappers and pipelines used to link tools with individual-level data are available on request; interested parties should contact A.J.S.

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Acknowledgements

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.).

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  1. These authors contributed equally: Isabell Brikell, Dorte Helenius, Robert Loughnan, Joel Mefford, Clare E. Palmer, Rebecca Walker.

Authors and Affiliations

  1. Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark

    Sonja LaBianca, Dorte Helenius, Jesper R. Gådin, Morten Krebs, Vivek Appadurai, Morteza Vaez, Andrés Ingason, Thomas M. Werge & Andrew J. Schork

  2. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark

    Sonja LaBianca, Isabell Brikell, Dorte Helenius, 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, Andrés Ingason, Søren Dalsgaard, Thomas M. Werge & Andrew J. Schork

  3. National Centre for Register-based Research, Department of Economics and Business Economics, Aarhus University, Aarhus, Denmark

    Isabell Brikell, Esben Agerbo, Marianne Giørtz Pedersen, Preben Bo Mortensen & Søren Dalsgaard

  4. Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA

    Robert Loughnan & Terry L. Jernigan

  5. Center for Population Neuroscience and Genetics, Laureate Institute for Brain Research, Tulsa, OK, USA

    Robert Loughnan

  6. Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA

    Joel Mefford, Daniel H. Geschwind & Noah Zaitlen

  7. Center for Human Development, University of California, San Diego, La Jolla, CA, USA

    Clare E. Palmer & Terry L. Jernigan

  8. Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA

    Rebecca Walker & Daniel H. Geschwind

  9. Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Rebecca Walker & Daniel H. Geschwind

  10. Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark

    Esben Agerbo, Marianne Giørtz Pedersen, Preben Bo Mortensen & Søren Dalsgaard

  11. Department of Biomedicine – Human Genetics, Aarhus University, Aarhus, Denmark

    Anders D. Børglum

  12. Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark

    Anders D. Børglum

  13. Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark

    David M. Hougaard

  14. Psychosis Research Unit, Aarhus University Hospital – Psychiatry, Aarhus, Denmark

    Ole Mors

  15. Copenhagen Mental Health Center, Mental Health Services Capital Region of Denmark Copenhagen, Copenhagen, Denmark

    Merete Nordentoft

  16. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Merete Nordentoft & Thomas M. Werge

  17. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    Kenneth S. Kendler

  18. Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA

    Kenneth S. Kendler

  19. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    Terry L. Jernigan

  20. Department of Radiology, University of California, San Diego, La Jolla, CA, USA

    Terry L. Jernigan

  21. Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Daniel H. Geschwind

  22. Section of Genetic Medicine, University of Chicago, Chicago, IL, USA

    Andrew W. Dahl

  23. Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA

    Andrew J. Schork

Authors
  1. Sonja LaBianca
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  2. Isabell Brikell
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Contributions

S.L., I.B., S.D., T.M.W. and A.J.S. conceived the study. S.D., T.M.W. and A.J.S. supervised the study. S.L., I.B. and A.J.S. are responsible for overall study design, with several components of the manuscript carried out with input and guidance from collaborators. S.L., I.B. and D.H. extracted and defined the data from the registers, assisted and guided by E.A., M.G.P. and S.D. S.L. and A.J.S. conducted the SNP heritability, genetic correlations, GWAS and PGS generation, with assistance from J.R.G., V.A., M.V. and A.I. They were supervised by A.J.S. S.L. conducted the functional annotations, with assistance, design and supervision from R.W., D.H.G. and A.J.S. S.L., J.M. and A.J.S. conducted the single-locus and polygenic multinomial tests, using a statistical implementation from A.W.D. and N.Z., and supervised by A.W.D., N.Z. and A.J.S. R.L. and C.E.P. designed and conducted the analysis of the ABCD data and were supervised by T.L.J. A.J.S. conducted the simulations, with support from S.L., M.K. and K.S.K. A.D.B., D.M.H., O.M., M.N., P.B.M. and T.M.W. contributed the iPSYCH data. T.L.J. contributed the ABCD data. S.L. wrote the initial manuscript draft. S.L., I.B. and A.J.S. wrote subsequent versions of the manuscript. All authors discussed the results, commented on the drafts and provided critical feedback throughout.

Corresponding authors

Correspondence to Thomas M. Werge or Andrew J. Schork.

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The authors declare no competing interests.

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Nature Genetics thanks Evangelos Vassos and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Supplementary information

Supplementary Information

Supplementary Notes and Figs. 1–43.

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Supplementary Tables 1–29.

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LaBianca, S., Brikell, I., Helenius, D. et al. Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder. Nat Genet 56, 234–244 (2024). https://doi.org/10.1038/s41588-023-01593-7

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