☆ 4.8 Article

Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

NATURE COMMUNICATIONS (2021)

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Journal

NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-020-20443-2

Keywords

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Categories

Multidisciplinary Sciences

Funding

  1. Lundbeck Foundation [R165-2013-15320, R102-A9118, R155-2014-1724, R248-2017-2003]
  2. EU FP7 Program [602805]
  3. H2020 Program [667302]
  4. NIMH [1U01MH109514-01]
  5. Universities and University Hospitals of Aarhus and Copenhagen
  6. Novo Nordisk Foundation
  7. European Union's Seventh Framework Programme for research, technological development and demonstration [602805, 728018]
  8. personal Vici grant of the Dutch Organisation for Scientific Research [016-130-669]
  9. Dutch National Science Agenda for the NWA NeurolabNL project [400 17 602]
  10. Stanley Center for Psychiatric Research
  11. National Institute of Mental Health [5U01MH109539]
  12. Spanish 'Ministerio de Economia y Competitividad' [SAF2015-68341-R, RTI2018-100968-B-I00]
  13. AGAUR, 'Generalitat de Catalunya' [2017-SGR-738]
  14. European Union FP7 [602805]
  15. H2020 Programs [667302, 728018]
  16. Instituto de Salud Carlos III [PI15/01789, PI16/01505, PI17/00289, PI18/01788]
  17. European Regional Development Fund (ERDF)
  18. Fundacio La Marato de TV3 [092330/31]
  19. Agencia de Gestio d'Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya, Spain [2017SGR1461]
  20. Health Research and Innovation Strategy Plan [PERIS SLT006/17/287]
  21. Generalitat de Catalunya, Spain
  22. European College of Neuropsychopharmacology (ECNP network: 'ADHD across the lifespan')
  23. Departament de Salut, Generalitat de Catalunya, Spain
  24. NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation
  25. European Union Seventh Framework Program [602805]
  26. European Union H2020 Programme [667302, 728018]
  27. Instituto de Salud Carlos III, Spain [CP09/00119, CPII15/00023]
  28. Lundbeck Foundation (iPSYCH grant) [R102-A9118, R155-2014-1724, R248-2017-2003]
  29. National Institute of Health (R01) [ES026993]
  30. Novo Nordisk Foundation [22018]
  31. European Commission (Horizon 2020) [667302]
  32. Tryg Foundation [109399]
  33. Helsefonden [19-8-0260]
  34. Shire/Takeda
  35. AACAP
  36. Feinstein Institute for Medical Research, Food & Drug Administration
  37. Genentech
  38. Headspace Inc.
  39. NIDA
  40. Pfizer Pharmaceuticals
  41. Roche TCRC Inc.
  42. Sunovion Pharmaceuticals Inc.
  43. Takeda/Shire Pharmaceuticals Inc.
  44. Tris
  45. NIH
  46. MRC [G0300189] Funding Source: UKRI

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This study identified three genome-wide significant loci for ADHD comorbid with DBDs, with one locus on chromosome 11 found to be a strong risk locus across European and Chinese ancestries. The findings suggest an increased load of common risk variants in ADHD+DBDs compared to ADHD without DBDs, particularly in association with aggressive behavior.
Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD+DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD+DBDs across European and Chinese ancestries (rs7118422, P=3.15x10(-10), OR=1.17). We find a higher SNP heritability for ADHD+DBDs (h(SNP)(2)=0.34) when compared to ADHD without DBDs (h(SNP)(2)=0.20), high genetic correlations between ADHD+DBDs and aggressive (r(g)=0.81) and anti-social behaviors (r(g)=0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD+DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD+DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior. ADHD is often found to be comorbid with disruptive behavior disorders, but the genetic loci underlying this comorbidity are unknown. Here, the authors have performed a GWAS meta-analysis of ADHD with disruptive behavior disorders, finding three genome-wide significant loci in Europeans, and replicating one in a Chinese cohort.

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