Altres ajuts: This study is part of the International Multicentre persistent ADHD Collaboration (IMpACT). IMpACT unites major research centers working on the genetics of ADHD persistence across the lifespan and has participants in The Netherlands, Germany, Spain, Norway, the United Kingdom, the United States, Brazil and Sweden. Principal investigators of IMpACT are: Barbara Franke (chair), Andreas Reif (co-chair), Stephen V. Faraone, Jan Haavik, Bru Cormand, Antoni Ramos Quiroga, Philip Asherson, Klaus-Peter Lesch, Jonna Kuntsi, Claiton Bau, Jan Buitelaar, Stefan Johansson, Henrik Larsson, Alysa Doyle and Eugenio Grevet. IMpACT-NL: The Dutch IMpACT study is supported by grants from the Netherlands Organization for Scientific Research (NWO), i.e. the NWO Brain & Cognition Excellence Program (grant 433-09-229) and a Vici grant to BF (grant 016-130-669), and by grants from the Netherlands Brain Foundation (grant 15F07[2]27) and BBMRI-NL (grant CP2010-33). The research leading to these results also received funding from the European Community's Seventh Framework Programme (FP7/2007 - 2013) under grant agreements no. 602805 (Aggressotype) and no. 602450 (IMAGEMEND), and from the European Community's Horizon 2020 Programme (H2020/2014-2020) under grant agreement no. 643051 (MiND). In addition, the work was supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. NeuroIMAGE: This study used the sample from the NeuroIMAGE project. NeuroIMAGE was performed between 2009 and 2012, and is the follow-up study of the Dutch part of the International Multisite ADHD Genetics (IMAGE) project, a multisite, international effort. Funding support for the IMAGE project was provided by NIH grants R01MH62873 and R01MH081803 to Dr Faraone. This work was further supported by an NWO Large Investment Grant 1750102007010 and NWO Brain & Cognition an Integrative Approach grant (433-09-242) (to Dr Buitelaar), and grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and VU University Amsterdam. NeuroIMAGE also receives funding from the European Community's Seventh Framework Programme (FP7-/2007-2013) under grant agreement no. 278948 (TACTICS), no. 602805 (Aggressotype) and no. 602450 (IMAGEMEND). Nijmegen Biomedical Study (NBS): The NBS is a population-based survey conducted at the Department for Health Evidence, and the Department of Laboratory Medicine of the Radboud university medical center. Principal investigators of the Nijmegen Biomedical Study are Lambertus Kiemeney, André Verbeek, Dorine Swinkels and Barbara Franke. The NBS data are managed by the NBS project team and are available upon request; see www.nijmegenbiomedischestudie.nl for an overview of the data available in this study. Current practical coordinator of the NBS is Dr T.E. Galesloot. Readers can contact her to request the data (Tessel.Galesloot@radboudumc.nl). This research was financially supported by BBMRI-NL, a Research Infrastructure financed by the Dutch government VF is supported by the K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 602805, Aggressotype) and European Community's H2020 Programme (under grantagreements 643051, MiND, and 667302, CoCA).

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF⩾1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E−06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P =4.46E−08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P =6.47E−07); the PSD locus (P =7.58E−08) and ZCCHC4 locus (P =1.79E−06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P =1.61E−05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.