Meta-analysis of Genome wide Association Studies on Childhood ADHD Symptoms and Diagnosis Reveals 17 Novel Loci and 22 Potential Effector Genes

Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder for which genetic factors explain up to 75% of the variance. In this study, we performed a genome-wide association meta-analysis (GWAMA) of ADHD symptom measures, with an effective sample size of 120,092 (71,733 unique individuals from 28 population-based cohorts, with 288,887 quantitative ADHD symptom measures). Next, we meta-analyzed the results with a genome-wide association study (GWAS) of ADHD diagnosis. The GWAMA of ADHD symptoms returned no genome-wide significant variants. However, we estimated strong genetic correlations between our study of quantitative ADHD symptoms and the earlier study of ADHD diagnosis ( r g= 1.00, SE= 0.06). Moderate negative genetic correlations ( r g< -0.40) were observed with several cognitive traits. Genetic correlations between ADHD and aggressive behavior and antisocial behavior were around 1. This provides further evidence of the wide pleiotropic effects of genetic variants and the role that genetic variants play in the co-occurrence with (mental) health traits. The GWAMAs of ADHD symptoms and diagnosis identified 2,039 genome-wide significant variants, representing 39 independent loci, of which 17 were new. Using a novel fine-mapping and functional annotation method, we identified 22 potential effector genes which implicate several new potential biological processes and pathways that may play a role in ADHD. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts in large-scale GWAS can be useful to identify novel genes implicated in ADHD and related symptoms. ### Competing Interest Statement J.A.R.Q. was on the speakers bureau and/or acted as consultant for Biogen, Idorsia, Casen-Recordati, Janssen-Cilag, Novartis, Takeda, Bial, Sincrolab, Neuraxpharm, Novartis, BMS, Medice, Rubio, Uriach, Technofarma and Raffo in the last 3 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Idorsia, Janssen-Cilag, Rubio, Takeda, Bial and Medice. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 3 years: Exeltis, Idorsia, Janssen-Cilag, Neuraxpharm, Oryzon, Roche, Probitas and Rubio. M.C. has received fees to give talks for TAKEDA and Laboratorios RUBIO. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. ### Clinical Protocols ### Funding Statement The project was supported by the Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768. Cohort-specific acknowledgements and funding information are included in the Supplementary text. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Study approval was obtained from the Central Ethics Committee on Research Involving Human Subjects of the VU University Medical Center, Amsterdam (NTR 25th of May 2007 and ACTION 2013/41 and 2014.252), an Institutional Review Board certified by the U.S. Office of Human Research Protections (IRB number IRB00002991 under Federal-wide Assurance-FWA00017598; IRB/institute codes). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at