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

Nature Genetics volume 54, pages 1470–1478 (2022)Cite this article

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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.

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Fig. 1: Manhattan plots for GWAS and TWAS results.
Fig. 2: Comparison of PRS profiles across ADHD and ASD subtypes for 15 traits and/or phenotypes that have shown significant genetic correlations with ADHD and ASD in the past.

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Data availability

Summary statistics from this publication are available at http://ipsych.au.dk/downloads/. Summary statistics for the original ADHD and ASD GWAS analyses are available at the same site. For access to genotypes from the PGC samples and the iPSYCH sample, researchers should contact the lead PIs E.R. and/or A.B. (https://pgc.unc.edu/for-researchers/working-groups/autism-working-group/) for PGC-ASD; A.B. for iPSYCH-ASD; B.N. and/or B.F. (https://pgc.unc.edu/for-researchers/working-groups/adhd-working-group/) for PGC-ADHD; and A.B. for iPSYCH-ADHDy. Data used for generation of the brain transcriptome model are available from PsychENCODE (overview of available datasets at http://resource.psychencode.org/); genotypes are controlled data and access instructions are provided at https://www.synapse.org/#!Synapse:syn4921369/wiki/477467. Note that some datasets were indirectly accessed at the respective analytical websites (for example, GSE76381 through the FUMA website). Please refer to these websites (for example, for FUMA, https://fuma.ctglab.nl/links and https://fuma.ctglab.nl/tutorial#datasets) for availability of datasets used in the respective follow-up analyses and/or lookups (for example, GSE76381).

Code availability

Please refer to individual sections of the methods above for published code (for example, for EpiXcan or Ricopili). As the in-house scripts used for data processing and analysis of the iPSYCH data on the GenomeDK HPC infrastructure are highly dependent on that context, they can only be obtained from the authors upon request. This way we can ensure the proper context is explained in dialog with the interested parties.

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Acknowledgements

The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the EU H2020 Program (grant no. 667302, CoCA), 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.). G.V. was funded by NIMH grant K08MH122911 and the 2020 NARSAD Young Investigator Grant no. 29350 from the Brain & Behavior Research Foundation. P.R. was funded by NIMH grants R01MH125246, U01MH116442 and R01MH109677. Support for this research was further received by B.C. from the Spanish Ministerio de Ciencia, Innovación y Universidades (RTI2018-100968-B-100), Ministerio de Economía y Competitividad, AGAUR/Generalitat de Catalunya (2017-SGR-738), the European Union H2020 Program (H2020/2014-2020) under grant agreements 667302 (CoCA), 643051 (MiND) and 728018 (Eat2beNICE), and the ECNP network ‘ADHD across the lifespan’. S.V.F. is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreements 667302 and 965381; NIMH grants U01MH109536-01, U01AR076092-01A1, R0MH116037 and 5R01AG06495502; Oregon Health and Science University, Otsuka Pharmaceuticals and Supernus Pharmaceutical Company. We thank all participants in the cohorts included in this analysis.

Author information

Author notes

  1. These authors contributed equally: Manuel Mattheisen, Jakob Grove, Thomas D. Als, Joanna Martin.

Authors and Affiliations

  1. Department of Biomedicine - Human Genetics and the iSEQ Center, Aarhus University, Aarhus, Denmark

    Manuel Mattheisen, Jakob Grove, Thomas D. Als, Sandra Meier, Ditte Demontis, Nora I. Strom & Anders D. Børglum

  2. Department of Community Health and Epidemiology & Department of Psychiatry, Dalhousie University, Halifax, NS, Canada

    Manuel Mattheisen & Sandra Meier

  3. Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany

    Manuel Mattheisen & Nora I. Strom

  4. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark

    Jakob Grove, Thomas D. Als, Ditte Demontis, Anders Rosengren, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Esben Agerbo, Merete Nordentoft, Thomas Werge, Ole Mors, David M. Hougaard, Preben B. Mortensen & Anders D. Børglum

  5. Center for Genomics and Personalized Medicine, Aarhus, Denmark

    Jakob Grove, Thomas D. Als, Ditte Demontis, Preben B. Mortensen & Anders D. Børglum

  6. Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark

    Jakob Grove

  7. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK

    Joanna Martin

  8. Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Georgios Voloudakis, Jaroslav Bendl, Mads Engel Hauberg, Biao Zeng, Gabriel Hoffman, Wen Zhang & Panos Roussos

  9. Icahn Institute for Data Science and Genomic Technology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Georgios Voloudakis, Jaroslav Bendl, Mads Engel Hauberg, Biao Zeng, Gabriel Hoffman, Wen Zhang & Panos Roussos

  10. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Georgios Voloudakis, Jaroslav Bendl, Mads Engel Hauberg, Biao Zeng, Gabriel Hoffman, Wen Zhang, Joseph D. Buxbaum & Panos Roussos

  11. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Raymond Walters, Caitlin E. Carey, Elise B. Robinson, Benjamin M. Neale & Mark J. Daly

  12. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Raymond Walters, Caitlin E. Carey, Elise B. Robinson, Benjamin M. Neale & Mark J. Daly

  13. Institute of Biological Psychiatry, Mental Health Services Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark

    Anders Rosengren & Thomas Werge

  14. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Nora I. Strom

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

    Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen & David M. Hougaard

  16. National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark

    Esben Agerbo, Søren Dalsgaard & Preben B. Mortensen

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

    Esben Agerbo & Preben B. Mortensen

  18. Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Catalonia, Spain

    Bru Cormand

  19. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain

    Bru Cormand

  20. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain

    Bru Cormand

  21. Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia, Spain

    Bru Cormand

  22. Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark

    Merete Nordentoft & Thomas Werge

  23. Copenhagen Research Centre for Mental Health (CORE), Mental Health Centre Copenhagen, Copenhagen, Denmark

    Merete Nordentoft

  24. University Hospital, Hellerup, Denmark

    Merete Nordentoft

  25. GLOBE Institute, Center for GeoGenetics, University of Copenhagen, Copenhagen, Denmark

    Thomas Werge

  26. Psychosis Research Unit, Aarhus University Hospital-Psychiatry, Aarhus, Denmark

    Ole Mors

  27. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Joseph D. Buxbaum

  28. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Joseph D. Buxbaum

  29. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Joseph D. Buxbaum & Panos Roussos

  30. Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, NY, USA

    Stephen V. Faraone

  31. Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY, USA

    Stephen V. Faraone

  32. Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

    Barbara Franke

  33. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

    Barbara Franke

  34. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Elise B. Robinson

  35. Department of Psychiatry, JJ Peters VA Medical Center, Bronx, NY, USA

    Panos Roussos

  36. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Mark J. Daly

  37. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

    Mark J. Daly

Authors
  1. Manuel Mattheisen
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  2. Jakob Grove
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  3. Thomas D. Als
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  4. Joanna Martin
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  14. Biao Zeng
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  15. Gabriel Hoffman
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  16. Wen Zhang
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  19. Esben Agerbo
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  34. Anders D. Børglum
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Contributions

M.M., J.G. and A.D.B. designed the study. M.M., J.G., T.D.A., J.M., G.V., S.M., D.D., J.B., R.W., C.E.C., A.R., N.I.S., W.Z., M.E.H., B.Z. and G.H. conducted data analysis. P.B.M., E.B.R., P.R., B.M.N., M.J.D. and A.D.B. supervised data analysis. J.B.-G., M.B.-H., E.A., J.D.B., M.N., T.W., O.M., D.M.H., P.B.M., B.M.N., M.J.D. and A.D.B. provided data. M.M., J.G., T.D.A., J.M., S.M. and A.D.B. wrote the paper. M.M., J.G., T.D.A., J.M., B.C., E.B.R., S.V.F., B.F., S.D. and A.D.B. formed the core revision group. A.D.B. directed the study. All authors discussed the results and approved the final version of the manuscript.

Corresponding authors

Correspondence to Manuel Mattheisen or Anders D. Børglum.

Ethics declarations

Competing interests

B.F. has received educational speaking fees from Medice. In the past year, S.V.F. has received income, potential income, travel expenses, continuing education support and/or research support from Takeda, OnDosis, Tris, Otsuka, Arbor, Ironshore, Rhodes, Akili Interactive Labs, Sunovion, Supernus and Genomind. With his institution, S.V.F. has US patent US20130217707 A1 for the use of sodium–hydrogen exchange inhibitors in the treatment of ADHD. S.V.F. also receives royalties from books published by Guilford Press (Straight Talk about Your Child’s Mental Health), Oxford University Press (Schizophrenia: The Facts) and Elsevier (ADHD: Non-Pharmacologic Interventions). S.V.F. is Program Director of www.adhdinadults.com. B.M.N. is a member of the scientific advisory board at Deep Genomics and Neumora (formerly Neumora) and consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen. M.J.D. is a founder of Maze Therapeutics and is on the Scientific Advisory Board of RBNC Therapeutics. The other authors declare no competing interests.

Peer review

Peer review information

Nature Genetics thanks E. Byrne, Andreas G. Chiocchetti 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 Note and Figs. 1–14.

Reporting Summary

Peer Review File

Supplementary Data 1

PheWAS lookup for combined GWAS in data from the OpenGWAS project.

Supplementary Data 2

Lookup for combined (ADHD or ASD) and differentiating (ADHD versus ASD) GWAS top SNPs in results from recent studies.

Supplementary Data 3

Lookup for combined (ADHD or ASD) and differentiating (ADHD versus ASD) GWAS top SNPs in results from GWAS in comorbid cases (ADHD and ASD), ADHD-only cases and ASD-only cases (all versus controls).

Supplementary Data 4

TWAS results for combined and ADHD versus ASD GWAS.

Supplementary Data 5

Gene-based analyses results for combined GWAS and ADHD versus ASD GWAS.

Supplementary Data 6

LD Hub analyses for original GWAS in ADHD, ASD and GWAS of combined dataset and ADHD versus ASD.

Supplementary Data 7

PheWAS lookup for ADHD versus ASD GWAS in data from the OpenGWAS project.

Supplementary Data 8

LDSC enrichment analyses for epigenomic peaks.

Supplementary Data 9

Genetic correlations for autism subtypes with ADHD.

Supplementary Data 10

FUMA functional annotation information using FUMA v.1.3.6a.

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Mattheisen, M., Grove, J., Als, T.D. et al. Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups. Nat Genet 54, 1470–1478 (2022). https://doi.org/10.1038/s41588-022-01171-3

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