The iPSYCH study was approved by the Scientific Ethics Committee in the Central Denmark Region (case number 1-10-72-287-12) and the Danish Data Protection Agency. In accordance with Danish legislation, the above-mentioned ethics committee waived the need for specific informed consent in biomedical research based on existing biobanks. iPSYCH was approved by the ethics committee in 2012, with subsequent amendments in 2013, 2015 and 2018. More details can be found at https://ipsych.dk/en/data-security/health-research-and-ethical-approval. New Danish legislation (effective from January 2024) introduces the possibility for participants to opt out of studies that are exempt from active informed consent. After consulting with the Ethics Committees and patient organizations, iPSYCH contacted all participants (around 140,000) in the iPSYCH cohort in June 2025 and offered the possibility of opting out of new genetic studies initiated henceforth. Overall, 1.8% of the iPSYCH participants chose to opt out, and their data will be deleted from the active research database. Data included in finalized and ongoing studies will not be removed.
The clinical data were approved by the ethics committee at the University of Würzburg in Germany. In the Netherlands, they were approved by the regional ethics committee (Commissie Mensgebonden Onderzoek: CMO Regio Arnhem—Nijmegen; protocol III.04.0403 and 2014/290; ABR: NL47721.091.14) and the Institutional Review Board of the Radboud University Medical Center. Participants were included at the Department of Psychiatry at the Radboud University Nijmegen Medical Centre. All participants in the German and Dutch samples provided signed informed consent in accordance with the Declaration of Helsinki.
Samples
iPSYCH
The individuals selected for exome sequencing were part of the iPSYCH cohort, which has been described in detail elsewhere15,16. In short, the study base includes all singleton births to mothers who were living in Denmark between 1 May 1981 and 31 December 2008, where the child was alive and resided in Denmark at their one-year birthday (n = 1,657,449). All individuals diagnosed with major psychiatric disorders by the end of 2016 according to the ICD10 criteria (ADHD (1.8% in the study base), autism, bipolar disorder, schizophrenia, major depressive disorder or post-partum depression (n = 93,608)) were identified in the study base using information in the Danish Psychiatric Central Research Registry49 (and the Danish Patient Registry50 for some disorders). In addition, 50,000 randomly selected population-based controls from the study base were selected. Subsequently, biological material for genotyping was obtained from the Danish Neonatal Screening Biobank (DNSB)51. The DNSB has stored residual biological material from screening of newborns for rare metabolic disorders since May 1981, and includes material from practically all births in Denmark since then. A subsample of 34,544 individuals was selected for whole-exome sequencing, and from these, we included individuals with an ICD10 diagnosis of ADHD (F90) in the Danish Psychiatric Central Research Registry49 and the Danish Patient Registry50 given before or during 2016; individuals with no diagnosis of the major psychiatric disorders (autism (ICD10: F84.0, F84.1, F84.5, F84.8 and F84.9), bipolar disorder (ICD10: F30–F31), schizophrenia (ICD10: F20) or major depressive disorder (ICD10: F32–F33)) were included as controls. The samples were included in iPSYCH in 2012–2016 and the sequencing was performed in 2012–2018.
For the comorbidity analyses, we identified individuals with the following ICD10 diagnosis codes in the Danish Psychiatric Central Research Registry: ID (ICD10: F70, F71, F72, F73, F78 and F79); ASD (as above); schizophrenia (as above); DBDs (including conduct disorder and oppositional defiant disorder (ICD10: F91 and F90.1); SUDs (ICD10: F10.1–9, F11.1–9, F12.1–9, F13.1–9, F14.1–9, F15.1–9, F16.1–9, F17.1–9, F18.1–9 and F19.1–9) and multi-comorbidities, which, besides the comorbidities already listed, included comorbid anxiety (ICD10: F40.0–F40.2, F41.0–F41.1, F42 and F43.0–F43.1), tic disorder (ICD10: F95), bipolar disorder (ICD10: F30–F31), major depressive disorder (ICD10: F32–F33), anorexia nervosa (ICD10: F50.0), DDs (ICD10: F80–F83) and antisocial personality disorder (ICD10: F60.2).
Clinical samples
The clinical samples consisted of adults (over 18 years old) with persistent ADHD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria. None of the individuals was diagnosed with ID. They were recruited as part of the International Multicenter Persistent ADHD Collaboration (IMpACT) at two sites: Radboud University Medical Center, the Netherlands, and University Hospital Würzburg, Germany. In analyses of these clinical samples, we used control samples from individuals recruited together with the clinical cases at the IMpACT site at Radboud University Medical Center (ADHD-screened controls), and from 1,766 German control individuals who were recruited from the German MI Family Study52 and the Angio-Lub study; the latter samples were whole-exome-sequenced by the MIGen Exome Sequencing Consortium: Lubeck Heart Study (dbGaP accession number phs000990/DS-CVD, https://dbgap.ncbi.nlm.nih.gov/beta/study/phs000990.v1.p1/). The German controls consisted of 870 individuals with cardiovascular disease and 896 without. The total set of samples described in this section is referred to as the ‘clinical sample’ in the remainder of this manuscript.
GnomAD
All references to gnomAD refer to release 2.1.1 exomes from a subset of gnomAD consisting of individuals with non-Finnish European ancestry, and no diagnosis of psychiatric and neurological disorders (n = 44,779) (see ‘Data availability’).
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