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

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  • Ditte Demontis
  • Raymond K Walters
  • Veera M Rajagopal
  • Irwin D Waldman
  • Jakob Grove
  • Thomas D Als
  • Søren Dalsgaard
  • Marta Ribasés
  • Jonas Bybjerg-Grauholm
  • Maria Bækvad-Hansen
  • Thomas Werge
  • Merete Nordentoft
  • Ole Mors
  • Preben Bo Mortensen
  • ADHD Working Group of the Psychiatric Genomics Consortium (PGC)
  • Bru Cormand
  • David M Hougaard
  • Benjamin M Neale
  • Barbara Franke
  • Stephen V Faraone
  • Anders D Børglum
  • Hans-Christoph Steinhausen (Medlem af forfattergruppering)
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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 = 3.15×10 −10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h 2 SNP = 0.34) when compared to ADHD without DBDs (h 2 SNP = 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.

OriginalsprogEngelsk
Artikelnummer576
TidsskriftNature Communications
Vol/bind12
Udgave nummer1
DOI
StatusUdgivet - dec. 2021

Bibliografisk note

Funding Information:
The iPSYCH team was supported by grants from the Lundbeck Foundation (R165-2013-15320, R102-A9118, R155-2014-1724, and R248-2017-2003), the EU FP7 Program (Grant No. 602805, “Aggressotype”) and 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.). This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602805 (Aggressotype) and 728018 (Eat2beNICE). This work reflects only the authors’ views, and the European Union is not liable for any use that may be made of the information contained herein. Barbara Franke was supported by a personal Vici grant of the Dutch Organisation for Scientific Research (grant 016-130-669) and by a grant for the Dutch National Science Agenda for the NWA NeurolabNL project (grant 400 17 602). Raymond Walters was supported by the Stanley Center for Psychiatric Research and the National Institute of Mental Health (5U01MH109539). Bru Cormand received support from the Spanish ‘Ministerio de Economía y Competitividad’ [grant numbers SAF2015-68341-R, RTI2018-100968-B-I00], from AGAUR, ‘Generalitat de Catalunya’ [grant number 2017-SGR-738] and from the European Union FP7 [grant agreement n° 602805] and H2020 Programs [grant agreements n° 667302, 728018]. This work was also funded by Instituto de Salud Carlos III (PI15/01789, PI16/01505, PI17/00289, PI18/ 01788), and co-financed by the European Regional Development Fund (ERDF), from ‘Fundacio´ La Marato´ de TV3’ (ref. 092330/31), Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya, Spain (2017SGR1461), the Health Research and Innovation Strategy Plan (PERIS SLT006/17/287), Generalitat de Catalu-nya, Spain, the European College of Neuropsychopharmacology (ECNP network: ‘ADHD across the lifespan’), Departament de Salut, Generalitat de Catalunya, Spain, and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. The research leading to these results has also received funding from the European Union Seventh Framework Program (FP72007-2013) under grant agreement No 602805 (Agressotype) and from the European Union H2020 Programme (H2020/2014-2020) under grant agreements Nos. 667302 (CoCA) and 728018 (Eat2BeNICE). Marta RiBasés is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Spain (CP09/00119 and CPII15/00023). Dr. Dalsgaard’s research is supported by grants from The Lundbeck Foundation (iPSYCH grant no R102-A9118, R155-2014-1724 and R248-2017-2003), National Institute of Health (R01, grant no ES026993), Novo Nordisk Foundation (grant no 22018), the European Commission (Horizon 2020, grant no 667302), Tryg Foundation (109399) and Helsefonden (grant no 19-8-0260). We wish to acknowledge the collaboration with members of the Psychiatric Genomics Consortium - ADHD Working Group (including the iPSYCH-Broad Group) who are not overlapping with the contributing members from the consortium (listed in the Supplementary file). Thomas Werge has acted as scientific advisor to H. Lundbeck A/S. Eugenio Horacio Grevet has been in the speaker bureau and consultant board of Shire (now TAKEDA) in the last three years. Luis Augusto Rohde has received grant or research support from, served as a consultant to, and served on the speakers’ bureau of Medice, Novartis/Sandoz and Shire/Takeda in the last three years. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by Dr Rohde have received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Novartis/Sandoz and Shire/Takeda. Dr Rohde has received authorship royalties from Oxford Press and ArtMed and travel grants from Shire to take part in the 2018 APA annual meeting. Dr Ramos-Quiroga reports grants and personal fees from Takeda, grants and personal fees from Janssen, grants and personal fees from Roche, personal fees from Lilly, personal fees from Novartis, personal fees from Bial, personal fees from Shionogui, grants and personal fees from Lundbeck, grants and personal fees from Almirall, grants and personal fees from Braingaze, grants and personal fees from Sincrolab, personal fees from Medice, grants and personal fees from Rubio, and grants from Psious outside the submitted work. Henrik Larsson has served as a speaker for Evolan Pharma and Shire/ Takeda and has received research grants from Shire/Takeda; all outside the submitted work. Lindsey Kent, GMC: 3325726, The University of St Andrews is a registered charity in Scotland: No SCO13532. Dr. Biedermans disclosure statement for 2020 is as follows: Dr. Joseph Biederman is currently receiving research support from the following sources: AACAP, Feinstein Institute for Medical Research, Food & Drug Administration, Gen-entech, Headspace Inc., NIDA, Pfizer Pharmaceuticals, Roche TCRC Inc., Sunovion Pharmaceuticals Inc., Takeda/Shire Pharmaceuticals Inc., Tris, and NIH. Dr. Bieder-man’s program has received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Biomarin, Bracket Global, Cogstate, Ingenix, Medavent Prophase, Shire, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. In 2020: Through MGH corporate licensing, Dr. Biederman has a US Patent (#14/027,676) for a non-stimulant treatment for ADHD, a US Patent (#10,245,271 B2) on a treatment of impaired cognitive flexibility, and a patent pending (#61/233,686) on a method to prevent stimulant abuse. He receives honoraria from the MGH Psychiatry Academy for tuition-funded CME courses.

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