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Investigating Direct and Indirect Genetic Effects in Attention-Deficit/Hyperactivity Disorder Using Parent-Offspring Trios

  • Joanna Martin
    Correspondence
    Address correspondence to Joanna Martin, Ph.D.
    Affiliations
    MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom

    Wolfson Centre for Young People’s Mental Health, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
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  • Matthew Wray
    Affiliations
    MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
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  • Sharifah Shameem Agha
    Affiliations
    MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom

    Cwm Taf Morgannwg University Health Board, Wales, United Kingdom
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  • Katie J.S. Lewis
    Affiliations
    MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
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  • Richard J.L. Anney
    Affiliations
    MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
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  • Michael C. O’Donovan
    Affiliations
    MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
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  • Anita Thapar
    Affiliations
    MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom

    Wolfson Centre for Young People’s Mental Health, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
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  • Kate Langley
    Affiliations
    MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom

    School of Psychology, Cardiff University, Cardiff, United Kingdom
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Open AccessPublished:June 14, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.06.008

      Abstract

      Background

      Attention-deficit/hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e., direct) and nontransmitted (i.e., indirect) common variant risks. Using parent-offspring trios, we tested whether polygenic liability for neurodevelopmental and psychiatric disorders and lower cognitive ability is overtransmitted to ADHD probands. We also tested for indirect or genetic nurture effects by examining whether nontransmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative of the clinical ADHD population.

      Methods

      Polygenic risk scores (PRSs) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder, schizophrenia, Tourette syndrome, and cognitive ability were calculated in UK control subjects (n = 5081), UK probands with ADHD (n = 857), their biological parents (n = 328 trios), and also a replication sample of 844 ADHD trios.

      Results

      ADHD PRSs were overtransmitted and cognitive ability and obsessive-compulsive disorder PRSs were undertransmitted. These results were independently replicated. Overtransmission of polygenic liability was not observed for other disorders. Nontransmitted alleles were not enriched for ADHD liability compared with control subjects. Probands from incomplete trios had more hyperactive-impulsive and conduct disorder symptoms, lower IQ, and lower socioeconomic status than complete trios. PRS did not vary by trio status.

      Conclusions

      The results support direct transmission of polygenic liability for ADHD and cognitive ability from parents to offspring, but not for other neurodevelopmental/psychiatric disorders. They also suggest that nontransmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be nonrandom, in terms of demographic and clinical factors.

      Keywords

      Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, with robustly associated common genetic risk variants (
      • Demontis D.
      • Walters R.K.
      • Martin J.
      • Mattheisen M.
      • Als T.D.
      • Agerbo E.
      • et al.
      Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.
      ). It shares genetic liability with many other neurodevelopmental/psychiatric disorders, and lower cognitive ability/IQ (
      • Demontis D.
      • Walters R.K.
      • Martin J.
      • Mattheisen M.
      • Als T.D.
      • Agerbo E.
      • et al.
      Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.
      ,
      • Andersson A.
      • Tuvblad C.
      • Chen Q.
      • Du Rietz E.
      • Cortese S.
      • Kuja-Halkola R.
      • Larsson H.
      Research Review: The strength of the genetic overlap between ADHD and other psychiatric symptoms – A systematic review and meta-analysis.
      ,
      Cross-Disorder Group of the Psychiatric Genomics Consortium
      Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders.
      ). Parents of children with ADHD have a higher prevalence of ADHD and other neurodevelopmental/psychiatric disorders than the general population (
      • Thapar A.
      Discoveries on the genetics of ADHD in the 21st century: New findings and their implications.
      ,
      • Agha S.S.
      • Zammit S.
      • Thapar A.
      • Langley K.
      Are parental ADHD problems associated with a more severe clinical presentation and greater family adversity in children with ADHD?.
      ). Given that ADHD is highly heritable, cross-generational transmission is likely explained by genetic, rather than environmental, factors. However, parents provide the pre- and postnatal environment for their children, both of which have an effect on early development. It is well established that many environmental exposures are influenced by parental genotypes; known as gene-environment correlation (
      • Thapar A.
      • Rice F.
      Family-based designs that disentangle inherited factors from pre- and postnatal environmental exposures: In vitro fertilization, discordant sibling pairs, maternal versus paternal comparisons, and adoption designs.
      ). As such, it is possible that ADHD is influenced by parental genetic liability that is not transmitted to the child, via indirect or genetic nurture effects (e.g., via parenting behavior), in addition to transmitted or direct genetic risks.
      ADHD genetic studies frequently use a case-control design (
      • Demontis D.
      • Walters R.K.
      • Martin J.
      • Mattheisen M.
      • Als T.D.
      • Agerbo E.
      • et al.
      Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.
      ), but an alternative parent- offspring trio design (using data from an ADHD proband and both biological parents) is more suitable for certain research purposes. For example, trios can be used to identify inherited and noninherited genetic risk variants (
      • Martin J.
      • Hosking G.
      • Wadon M.
      • Agha S.S.
      • Langley K.
      • Rees E.
      • et al.
      A brief report: De novo copy number variants in children with attention deficit hyperactivity disorder.
      ). This design circumvents limitations of the case-control design, such as imperfect case-control matching on confounders (e.g., ancestry) and bias from the use of screened control subjects in cross-disorder genetic correlation estimates (
      • Kendler K.S.
      • Chatzinakos C.
      • Bacanu S.A.
      The impact on estimations of genetic correlations by the use of super-normal, unscreened, and family-history screened controls in genome wide case–control studies.
      ). More recently, the trio design has been extended to allow the study of transmission of total common variant liability from parents to offspring (
      • Weiner D.J.
      • Wigdor E.M.
      • Ripke S.
      • Walters R.K.
      • Kosmicki J.A.
      • Grove J.
      • et al.
      Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders.
      ), and to test the impact of indirect genetic effects or genetic nurture on children, by examining the contribution of nontransmitted alleles (
      • Kong A.
      • Thorleifsson G.
      • Frigge M.L.
      • Vilhjalmsson B.J.
      • Young A.I.
      • Thorgeirsson T.E.
      • et al.
      The nature of nurture: Effects of parental genotypes.
      ). Enriched ADHD polygenic liability in nontransmitted parental alleles could exert an effect on the proband through such an indirect genetic nurture path.
      The first aim of this study was to test whether polygenic risk scores (PRSs) (or the sum of each individual’s common variant liability) for ADHD, other neurodevelopmental/psychiatric disorders, and lower cognitive ability are overtransmitted from parents to children with ADHD (i.e., direct genetic effects). Given the high heritability of ADHD, we expected to observe overtransmission of risk alleles for ADHD and phenotypes with which ADHD shares genetic liability. This can be tested using the polygenic transmission disequilibrium test (pTDT), which compares proband PRS to the mean of their parents’ PRSs (i.e., the common variant liability expected in the proband by chance) (
      • Weiner D.J.
      • Wigdor E.M.
      • Ripke S.
      • Walters R.K.
      • Kosmicki J.A.
      • Grove J.
      • et al.
      Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders.
      ). Under the hypothesis that manifestation of ADHD depends on direct genetic effects, risk alleles must be transmitted to the proband more often than expected by chance, resulting in a proband PRS greater than the parental mean. When testing for shared cross-disorder genetic effects, this is a more stringent test than case-control analysis, given the limitations of case-control samples outlined above.
      The second aim was to investigate whether nontransmitted ADHD risk alleles are elevated in parents of children with ADHD, compared with population control subjects. Genome-wide association studies (GWASs) of trios use pseudo-control alleles, which represent the parental alleles that are not transmitted to offspring. If the parents have ADHD or multiple offspring with ADHD, these nontransmitted alleles could be enriched for ADHD liability compared with the general population, which could reduce genomic discovery power (
      • Peyrot W.J.
      • Boomsma D.I.
      • Penninx B.W.J.H.
      • Wray N.R.
      Disease and polygenic architecture: Avoid trio design and appropriately account for unscreened control subjects for common disease.
      ,
      • Klei L.
      • Sanders S.J.
      • Murtha M.T.
      • Hus V.
      • Lowe J.K.
      • Willsey A.J.
      • et al.
      Common genetic variants, acting additively, are a major source of risk for autism.
      ). Of even greater interest, nontransmitted alleles can exert indirect genetic effects on offspring phenotype (e.g., via the environment parents provide). Enrichment of ADHD risk in nontransmitted alleles compared with control subjects would be consistent with indirect or genetic nurture effects on offspring ADHD. Therefore, a better understanding of the factors influencing ADHD risk can help inform early intervention and prevention strategies. Such indirect effects may also exist for phenotypes that share genetic liability with ADHD (e.g., other neurodevelopmental/psychiatric disorders and lower cognitive ability).
      A final question was whether children with ADHD recruited into a trio design are representative of the wider clinical ADHD population. The need to obtain DNA from all 3 individuals in a parent-offspring trio could result in biased ascertainment. This can be a challenge because missing genetic information is unlikely to be missing at random (
      • Martin J.
      • Tilling K.
      • Hubbard L.
      • Stergiakouli E.
      • Thapar A.
      • Davey Smith G.
      • et al.
      Association of genetic risk for schizophrenia with nonparticipation over time in a population-based cohort study.
      ). Many children with ADHD do not live with both biological parents, with evidence that ADHD severity is linked to likelihood of a child’s being in a nonintact family (
      • Hurtig T.
      • Ebeling H.
      • Taanila A.
      • Miettunen J.
      • Smalley S.
      • McGough J.
      • et al.
      ADHD and comorbid disorders in relation to family environment and symptom severity.
      ,
      • Hurtig T.
      • Taanila A.
      • Ebeling H.
      • Miettunen J.
      • Moilanen I.
      Attention and behavioural problems of Finnish adolescents may be related to the family environment.
      ). Previous research by our group suggests that in cases in which fathers do not live with the family, or decline to take part in research, children are more likely to have the more severe DSM-IV combined subtype of ADHD and comorbid conduct disorder (CD) than those from intact families (
      • West A.
      • Langley K.
      • Hamshere M.L.
      • Kent L.
      • Craddock N.
      • Owen M.J.
      • et al.
      Evidence to suggest biased phenotypes in children with attention deficit hyperactivity disorder from completely ascertained trios.
      ). This could mean that probands from incomplete trios have higher genetic liability for ADHD (and related disorders), affecting the generalizability of studies ascertaining only trios, but this requires investigation.
      In this study, we tested the following hypotheses using a UK clinical sample of children diagnosed with ADHD and their biological parents: 1) children with ADHD disproportionately inherit liability for neurodevelopmental/psychiatric disorders and lower cognitive ability, 2) nontransmitted ADHD polygenic liability is elevated compared with control subjects (i.e., evidence of genetic nurture), and 3) children from incomplete trios have a more severe clinical profile and higher neurodevelopmental/psychiatric polygenic liability, than those from complete trios.

      Methods and Materials

      Sample Description

      Children and young people with ADHD (ages 5–18 years; hereafter referred to as probands) were recruited through child and adolescent psychiatry or pediatric outpatient clinics across Wales and England. Exclusion criteria were a clinical diagnosis of schizophrenia, history of epilepsy, brain damage, or known neurologic or genetic disorder. Inclusion criteria were a DSM-III-R/DSM-IV research-based diagnosis for ADHD, confirmed using the Child and Adolescent Psychiatric Assessment (
      • Angold A.
      • Prendergast M.
      • Cox A.
      • Harrington R.
      • Simonoff E.
      • Rutter M.
      The child and adolescent psychiatric assessment (CAPA).
      ), a semistructured diagnostic interview undertaken with parents by trained and supervised psychologists, which assesses DSM-IV inattentive and hyperactive-impulsive symptoms, 2 additional DSM-III-R symptoms, and impairment. Symptom pervasiveness across settings was confirmed using teacher reports [Child ADHD Teacher Telephone Interview (
      • Holmes J.
      • Lawson D.
      • Langley K.
      • Fitzpatrick H.
      • Trumper A.
      • Pay H.
      • et al.
      The Child Attention-Deficit Hyperactivity Disorder Teacher Telephone Interview (CHATTI): Reliability and validity.
      ), or Conners’ Teacher Rating Scale (
      • Conners C.K.
      • Sitarenios G.
      • Parker J.D.
      • Epstein J.N.
      Revision and restandardization of the Conners Teacher Rating Scale (CTRS-R): Factor structure, reliability, and criterion validity.
      )].
      Written informed consent was obtained from all parents and young people 16 to 18 years of age and assent was gained from probands <16 years of age. Study approval was obtained from the Northwest England and Wales Multicentre Research Ethics Committees.
      Inattentive and hyperactive-impulsive symptom scores were generated using DSM-IV criteria. Impairment was assessed using 8 items (home life, social interactions, community activities, school, sports/clubs, taking care of oneself, recreational activities, and handling responsibilities). Impairment occurring “sometimes” or “often” was coded as 1 and “never” or “rarely” coded as 0, and items were summed.
      The Child and Adolescent Psychiatric Assessment was also used to assess comorbid symptoms in the preceding 3 months, according to DSM-IV, including CD, oppositional defiant disorder, anxiety, and depression. Probands 12 years of age and older also completed the child version of the Child and Adolescent Psychiatric Assessment. A symptom was considered as present if either the parent or proband reported it. Total symptom scores for CD (9 items), oppositional defiant disorder (8 items), anxiety (12 items), and depression (8 items) were generated. Autistic traits were assessed using the parent-rated Social Communication Questionnaire (39 items) (
      • Rutter M.
      • Bailey A.
      • Lord C.
      Social Communication Questionnaire.
      ). Full-scale IQ was assessed using the Wechsler Intelligence Scale for Children (WISC), version III/IV (
      • Wechsler D.
      Wechsler Intelligence Scale for Children.
      ,
      • Wechsler D.
      Wechsler Intelligence Scale for Children.
      ). Probands with IQ < 70 were considered to have intellectual disability (ID).
      Socioeconomic variables (family income, parental educational attainment, and parental employment status) and family history of psychiatric disorders were assessed by parental questionnaire. Low income was defined as self-reported gross annual family income <£20,000 (equivalent ∼US$32,000). Parental low educational attainment was defined as parents having left school without qualifications (General Certificate of Secondary Education or equivalent) at age 16 years. Socioeconomic status (SES) was classified by the occupation of the main family wage earner using the UK Standard Occupation Classification (
      Office of National Statistics, Standard Occupational Classification 2000, The Stationary Office; London..
      ). Two SES categories were defined (low: unskilled workers/unemployed; medium/high: manual and nonmanual skilled/partially skilled workers and professional/managerial workers). Family history was based on reported information about first degree relatives (i.e., biological parents and full siblings). Three binary variables were derived, relating to the presence of ADHD, other neurodevelopmental problems (e.g., learning difficulties, dyslexia, dyspraxia), and broadly defined major psychiatric disorders (e.g., depression, bipolar disorder [BD], schizophrenia).

      Genetic Data

      A detailed description of the genetic data can be found in the Supplement. In brief, DNA samples were collected from probands and parents and genotyped, followed by rigorous quality control (QC) procedures. Parent-offspring relationships were confirmed using identity-by-descent analysis in PLINK. The study ascertained families of European ancestry, which was confirmed using principal components analysis. For complete trios, nontransmitted parental alleles were extracted using PLINK (function: --tucc).
      PRSs were calculated using common autosomal variants based on 9 large discovery GWASs of primarily European ancestry: ADHD (
      • Demontis D.
      • Walters R.K.
      • Martin J.
      • Mattheisen M.
      • Als T.D.
      • Agerbo E.
      • et al.
      Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.
      ), anxiety disorders (
      • Purves K.L.
      • Coleman J.R.I.
      • Meier S.M.
      • Rayner C.
      • Davis K.A.S.
      • Cheesman R.
      • et al.
      A major role for common genetic variation in anxiety disorders.
      ), autism spectrum disorder (ASD) (
      • Grove J.
      • Ripke S.
      • Als T.D.
      • Mattheisen M.
      • Walters R.K.
      • Won H.
      • et al.
      Identification of common genetic risk variants for autism spectrum disorder.
      ), BD (
      • Stahl E.A.
      • Breen G.
      • Forstner A.J.
      • McQuillin A.
      • Ripke S.
      • Trubetskoy V.
      • et al.
      Genome-wide association study identifies 30 loci associated with bipolar disorder.
      ), major depressive disorder (MDD) (
      • Wray N.R.
      • Ripke S.
      • Mattheisen M.
      • Trzaskowski M.
      • Byrne E.M.
      • Abdellaoui A.
      • et al.
      Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.
      ), schizophrenia (
      • Riple S.
      • Walters J.T.R.
      • O’Donovan M.C.
      Schizophrenia Working Group of the Psychiatric Genomics Consortium
      Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia.
      ), obsessive-compulsive disorder (OCD) (

      International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC), OCD Collaborative Genetics Association Studies (OCGAS) (2018): Revealing the complex genetic architecture of obsessive–compulsive disorder using meta-analysis. Mol Psychiatry 23:1181–1188.

      ), Tourette syndrome (
      • Yu D.
      • Sul J.H.
      • Tsetsos F.
      • Nawaz M.S.
      • Huang A.Y.
      • Zelaya I.
      • et al.
      Interrogating the genetic determinants of Tourette’s syndrome and other tic disorders through genome-wide association studies.
      ), and cognitive ability/IQ (
      • Savage J.E.
      • Jansen P.R.
      • Stringer S.
      • Watanabe K.
      • Bryois J.
      • de Leeuw C.A.
      • et al.
      Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.
      ).
      Comparison individuals were 5081 individuals from the Wellcome Trust Case Control Consortium (WTCCC) (a UK control population sample) not screened for ADHD or other psychiatric disorders (
      Wellcome Trust Case Control Consortium
      Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
      ). The sample has been used previously as control subjects for a GWAS including a subset of the current ADHD cases (
      • Demontis D.
      • Walters R.K.
      • Martin J.
      • Mattheisen M.
      • Als T.D.
      • Agerbo E.
      • et al.
      Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.
      ,
      • Stergiakouli E.
      • Hamshere M.
      • Holmans P.
      • Langley K.
      • Zaharieva I.
      • deCODE Genetics
      • et al.
      Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD.
      ). The ADHD sample (including the ADHD nontransmitted parental pseudo-genotypes) was merged with the population control subjects using shared single nucleotide polymorphisms.
      The discovery GWAS used to calculate PRS had no overlap with the target ADHD sample. For the merged ADHD-control sample, we obtained GWAS data excluding the control subjects, where possible (all except MDD and BD).
      PRSs were calculated using linkage disequilibrium-clumping in PLINK (
      • Purcell S.
      • Neale B.
      • Todd-Brown K.
      • Thomas L.
      • Ferreira M.A.
      • Bender D.
      • et al.
      PLINK: A tool set for whole-genome association and population-based linkage analyses.
      ) for 7 p value thresholds and the first principal component was extracted and analyzed for each discovery phenotype following the PRS-principal components analysis method, an approach that reduces overfitting, maintaining good power (
      • Coombes B.J.
      • Ploner A.
      • Bergen S.E.
      • Biernacka J.M.
      A principal component approach to improve association testing with polygenic risk scores.
      ); see details in the Supplement. PRSs in the merged ADHD-control sample were standardized using the control population mean and standard deviation. Otherwise, PRSs were standardized as z scores.
      PCAiR (
      • Conomos M.P.
      • Miller M.B.
      • Thornton T.A.
      Robust inference of population structure for ancestry prediction and correction of stratification in the presence of relatedness.
      ), a package that robustly estimates population structure while taking into account kinship information, was used to extract the top 10 principal components.

      Definition of Trio Status

      A total of 857 probands with ADHD (mean [SD] age = 10.4 [2.8] years; n = 119 [13.9%] female) from 825 families met inclusion criteria and passed QC. Complete trios (coded as 0) were defined as families in which both parents provided a DNA sample and were confirmed as the biological parents, regardless of whether both parents passed subsequent QC (n = 367). Incomplete trios (coded as 1) were families in which 1 or both parents did not provide a DNA sample (n = 454). In families in which both parents had provided DNA but 1 or both parents could not be genotyped because of low sample quality, the probands were unclassified, because parent-offspring relatedness could not be confirmed (n = 36).
      Additional filters were applied for the analyses of transmitted (pTDT) and nontransmitted alleles, as follows: probands were excluded if parental samples did not pass QC or if the whole trio was not genotyped on the same array. Only the oldest proband was included for families with multiple probands genotyped (n = 39 excluded). This resulted in a sample of 328 trios meeting inclusion criteria for the pTDT and the analysis of nontransmitted parental alleles.

      Analyses

      We tested for overtransmission of liability to ADHD, ASD, anxiety, BD, MDD, OCD, schizophrenia, and Tourette syndrome and undertransmission of liability to cognitive ability in complete trios using the pTDT (
      • Weiner D.J.
      • Wigdor E.M.
      • Ripke S.
      • Walters R.K.
      • Kosmicki J.A.
      • Grove J.
      • et al.
      Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders.
      ). This analysis tests whether, on average, the proband PRS deviates significantly from the parental midpoint PRS and is robust to population stratification and other potential confounders (e.g., SES).
      Next, we compared the ADHD PRSs in nontransmitted alleles to population control subjects. We also explored whether the PRSs for other neurodevelopmental/psychiatric disorders and cognitive ability differed between nontransmitted alleles and population control subjects.
      Finally, we compared probands from complete and incomplete trios, in terms of demographic variables, clinical symptoms, and socioeconomic variables, and the proband and mother’s PRS for ADHD and related phenotypes. Father’s PRS could not be compared because there were only 14 fathers in incomplete trios.
      The top 10 ancestry-based principal components were residualized out of the PRS prior to analysis (except for the pTDT). When comparing probands and mothers based on trio status, genotyping batch was also included as a covariate and we accounted for the presence of siblings by specifying family clusters and applying a sandwich estimator to estimate cluster-robust standard errors of regression coefficients. All analyses used generalized estimating equations implemented in the drgee package in R. False discovery rate correction for multiple testing was applied for the genetic analyses in the primary sample.

      Replication Analysis

      Independent data from the International Multicentre ADHD Genetics (IMAGE) study (
      • Neale B.M.
      • Lasky-Su J.
      • Anney R.
      • Franke B.
      • Zhou K.
      • Maller J.B.
      • et al.
      Genome-wide association scan of attention deficit hyperactivity disorder.
      ) were used for replication. The sample consisted of 844 complete trios of probands diagnosed with ADHD (mean [SD] age = 10.9 [2.8] years; n = 111 [13.2%] females). Only 616 complete trios matched the WTCCC control population sample ancestry for the analyses of nontransmitted parental alleles. See the Supplement for details. Replication analyses were not corrected for multiple tests because the results are only interpreted with regard to how they compare with the primary analyses.

      Results

      Polygenic Transmission

      PRSs for ADHD were overtransmitted (mean [SE] = 0.30 [0.06]) to probands. There was no evidence of overtransmission of risk alleles for other disorders (Figure 1A; Table S1). Polygenic liabilities for cognitive ability (−0.33 [0.05]) and OCD (−0.18 [0.05]) were undertransmitted. The cognitive ability results were not influenced by comorbid ID; after excluding 28 ADHD probands with ID, the results remained the same (−0.33 [0.05]).
      Figure thumbnail gr1
      Figure 1Mean deviation of proband polygenic risk scores from the midparent distribution (i.e., standard deviations away from the midparent distribution) in attention-deficit/hyperactivity disorder (ADHD) trios, using the (A) primary sample (n = 328 trios) and the (B) replication sample (n = 844 trios). p values indicate the probability that the mean of the polygenic transmission disequilibrium test (pTDT) deviation distribution is 0 (two-sided, 1-sample t test). Error bars indicate standard errors. ∗p < .05; ∗∗p < .01; ∗∗∗p < .001. p Values shown are corrected for multiple tests for primary analyses and raw p values are shown for the replication analyses. See for detailed results. ANX, anxiety disorders; ASD, autism spectrum disorder; BD, bipolar disorder; COG, cognitive ability; MDD, major depressive disorder; OCD, obsessive-compulsive disorder; SCZ, schizophrenia; TS, Tourette syndrome.
      The results were independently replicated for ADHD (0.20 [0.03]), cognitive ability (−0.06 [0.02]), and OCD (−0.08 [0.03]) PRSs (Figure 1B; Table S1). Analyses in the replication sample also indicated undertransmission of anxiety and schizophrenia PRSs, but this was not supported by primary analyses.

      Nontransmitted Parental Alleles

      Figure 2A displays the mean PRSs for 328 ADHD trios, separately for probands, mothers, fathers, and nontransmitted parental alleles, relative to the control population; see Table S2 for detailed results. There was no evidence supporting elevated ADHD PRS for nontransmitted parental alleles. Exploratory analyses also found little support for elevated nontransmitted parental PRS for other disorders or lower cognitive ability PRSs. PRSs of probands, fathers, and mothers were elevated for ADHD and lower for cognitive ability than control subjects. No significant differences were observed for other disorder PRSs.
      Figure thumbnail gr2
      Figure 2Mean polygenic risk scores in attention-deficit/hyperactivity disorder (ADHD) complete trios: (A) primary sample (n = 328) and (B) replication sample (n = 616), in probands (P), fathers (F), mothers (M), and nontransmitted parental alleles (NT), relative to the control population sample (bold horizontal line at y = 0). Note: Bipolar disorder and major depressive disorder could not be examined because of inclusion of the control population sample in the discovery genetic studies for those disorders. Error bars indicate standard errors. ∗p < .05; ∗∗p < .01; ∗∗∗p < .001. p Values shown are corrected for multiple tests for primary analyses and raw p values are shown for the replication analyses. See for detailed results. ANX, anxiety disorders; ASD, autism spectrum disorder; COG, cognitive ability; OCD, obsessive-compulsive disorder; SCZ, schizophrenia; TS, Tourette syndrome.
      Analyses in the replication sample are shown in Figure 2B and Table S2. The results of the primary analysis were replicated for ADHD PRSs. Cognitive ability PRSs were lower and ASD PRSs were elevated in probands compared with control subjects. Proband and mothers’ anxiety PRSs were elevated compared with control subjects. There was little evidence of elevated PRSs for nontransmitted parental alleles for any phenotypes compared with the control sample and no other group differences were observed.

      Complete and Incomplete Trios

      Analysis of 821 probands (complete trios: n = 367, incomplete trios: n = 454) indicated that those from incomplete trios were older, had more hyperactive-impulsive ADHD and CD symptoms, had lower IQ, and were more likely to meet diagnostic criteria for CD (Table 1). Other variables were similar between groups. Parents of probands from incomplete trios had lower educational attainment, annual family income, and SES based on occupation. There were no group differences in family history of neurodevelopmental/psychiatric disorders.
      Table 1Comparison of Probands From Complete (n = 367) and Incomplete (n = 454) Trios in Terms of Demographic, Clinical, Socioeconomic, and Family History Variables
      PhenotypeIncomplete Trios, Mean (SE) or n (%)Complete Trios, Mean (SE) or n (%)OR (95% CI)
      Probands from complete trios were coded as 0 and those from incomplete trios were coded as 1; therefore, OR > 1 can be interpreted as an increase of the variable in the probands from incomplete trios.
      p
      Proband Age
      Proband age is included as a covariate in all other analyses.
      10.70 (0.13)10.10 (0.15)1.07 (1.02–1.13)6.3 × 10−3
      p < .05.
      Inattentive Symptoms7.48 (0.08)7.27 (0.09)1.07 (0.98–1.17).11
      Hyperactive-Impulsive Symptoms7.82 (0.07)7.65 (0.08)1.12 (1.02–1.24).019
      p < .05.
      ADHD Impairment6.88 (0.07)6.69 (0.09)1.11 (0.99–1.24).087
      IQ82.90 (0.67)85.50 (0.71)0.99 (0.98–1.00).041
      p < .05.
      Autistic Traits13.50 (0.36)12.80 (0.46)1.02 (0.99–1.04).23
      Anxiety Symptoms1.02 (0.09)0.93 (0.10)1.03 (0.93–1.13).60
      Depressive Symptoms1.42 (0.07)1.21 (0.07)1.09 (0.98–1.22).11
      ODD Symptoms4.11 (0.11)3.90 (0.13)1.04 (0.98–1.10).19
      CD Symptoms1.53 (0.08)1.16 (0.09)1.12 (1.02–1.23).012
      p < .05.
      Proband Sex, Male72 (15.9%)46 (12.5%)1.35 (0.91–2.01).13
      Low Family Income212 (72.4%)105 (50.5%)2.64 (1.78–3.90)1.3 × 10−6
      p < .05.
      Low Parental Education100 (31.6%)47 (21.9%)1.67 (1.10–2.52).015
      Low Family SES230 (59.9%)125 (39.1%)2.35 (1.71–3.22)1.1 × 10−7
      p < .05.
      Intellectual Disability58 (13.6%)29 (8.2%)1.27 (1.00–1.61).055
      CD Diagnosis107 (23.7%)60 (16.4%)1.51 (1.05–2.18).025
      p < .05.
      Family History
       ADHD75 (23.7%)60 (25.0%)0.92 (0.60–1.42).71
       Other NDs40 (12.9%)32 (13.4%)0.95 (0.56–1.60).84
       Major psychiatric disorders139 (42.4%)89 (37.4%)1.24 (0.87–1.77).24
      ADHD, attention-deficit/hyperactivity disorder; CD, conduct disorder; NDs, neurodevelopmental disorders; ODD, oppositional defiant disorder; OR, odds ratio; SES, socioeconomic status.
      a Probands from complete trios were coded as 0 and those from incomplete trios were coded as 1; therefore, OR > 1 can be interpreted as an increase of the variable in the probands from incomplete trios.
      b Proband age is included as a covariate in all other analyses.
      c p < .05.
      Analysis of probands’ and mothers’ PRSs indicated several nominally significant effects (Table 2). Probands from incomplete trios had higher BD and OCD PRSs, and higher maternal ADHD PRSs. On the contrary, mothers’ schizophrenia PRSs were lower in incomplete trios. However, these effects did not withstand multiple testing correction.
      Table 2Comparison of Polygenic Risk Scores in Probands and Mothers From Complete (n = 367)
      Genetic data were available for 344 mothers from complete trios and 269 mothers from incomplete trios.
      and Incomplete (n = 454) Trios
      PRSOR (95% CIs)ppFDR
      Proband’s PRS
       ADHD1.31 (0.94–1.82).12.27
       ANX1.11 (0.79–1.54).55.62
       ASD0.86 (0.62–1.17).33.54
       BD1.32 (1.03–1.69).026.21
       COG0.86 (0.58–1.26).43.58
       MDD1.38 (0.87–2.18).17.34
       OCD1.35 (1.00–1.81).047.21
       SCZ0.93 (0.70–1.22).60.64
       TS1.29 (0.98–1.70).073.23
      Mother’s PRS
       ADHD1.59 (1.06–2.40).026.21
       ANX1.26 (0.74–2.15).40.58
       ASD1.30 (0.62–2.72).48.58
       BD0.72 (0.50–1.04).078.23
       COG1.08 (0.64–1.82).77.77
       MDD1.58 (0.80–3.15).19.34
       OCD1.21 (0.73–2.00).45.58
       SCZ0.59 (0.36–0.97).038.21
       TS1.37 (0.95–1.98).097.25
      ADHD, attention-deficit/hyperactivity disorder; ANX, anxiety disorders; ASD, autism spectrum disorder; BD, bipolar disorder; COG, cognitive ability; FDR, false discovery rate; MDD, major depressive disorder; OCD, obsessive-compulsive disorder; OR, odds ratio; PRS, polygenic risk score; SCZ, schizophrenia; TS, Tourette syndrome.
      a Genetic data were available for 344 mothers from complete trios and 269 mothers from incomplete trios.

      Discussion

      We used a parent-offspring ADHD trio sample to test 3 hypotheses: overtransmission of polygenic liability from parents to probands, elevated polygenic liability in nontransmitted parental alleles, and nonrepresentativeness of ADHD trios. We found robust evidence of overtransmission of ADHD and lower cognitive ability polygenic liability and evidence of undertransmission of OCD PRSs. This was replicated in an independent ADHD sample and consistent with case-control analysis. We found limited evidence of overtransmission or case-control differences for other disorder PRSs. Parental nontransmitted alleles related to ADHD and other phenotypes were not elevated compared with a control population; i.e., we observed no evidence of genetic nurture. Finally, we observed several clinical and socioeconomic differences between probands from complete and incomplete trios, but no robust differences in PRSs.
      Overtransmission of ADHD polygenic liability, while not previously tested in ADHD using the pTDT, was expected. Interestingly, the magnitude of the effect sizes observed for ADHD and cognitive ability were similar in the primary sample, despite differences in size and genetic architecture of these discovery GWASs. ADHD is strongly associated with lower cognitive ability, and twin studies have shown a genetic correlation of 91% between ADHD and ID (
      • Faraone S.V.
      • Ghirardi L.
      • Kuja-Halkola R.
      • Lichtenstein P.
      • Larsson H.
      The familial co-aggregation of attention-deficit/hyperactivity disorder and intellectual disability: A register-based family study.
      ). Excluding 28 probands with ID did not affect the results. These results were replicated in an independent and larger ADHD sample from various European countries, although the effect sizes were smaller, particularly for cognitive ability. The primary sample’s IQ was lower than the population average (mean [SE] = 84.2 [0.48]), as expected for ADHD (
      • Kuntsi J.
      • Eley T.C.
      • Taylor A.
      • Hughes C.
      • Asherson P.
      • Caspi A.
      • Moffitt T.E.
      Co-occurrence of ADHD and low IQ has genetic origins.
      ). The mean IQ of the replication sample was comparable to the population average (100.4 [0.66]), and only 10 probands had IQ of <70, which could explain the lower effect size observed. However, the replicated result suggests that overtransmission of lower cognitive ability polygenic liability is not entirely explained by individuals with lower IQ.
      Previous estimates of genetic correlation between ADHD and cognitive ability (rg = −0.41) are of a similar magnitude to those between ADHD and MDD (rg = 0.42), ASD (rg = 0.36), and anxiety (rg = 0.33) (
      • Demontis D.
      • Walters R.K.
      • Martin J.
      • Mattheisen M.
      • Als T.D.
      • Agerbo E.
      • et al.
      Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.
      ,
      • Purves K.L.
      • Coleman J.R.I.
      • Meier S.M.
      • Rayner C.
      • Davis K.A.S.
      • Cheesman R.
      • et al.
      A major role for common genetic variation in anxiety disorders.
      ,
      • Grove J.
      • Ripke S.
      • Als T.D.
      • Mattheisen M.
      • Walters R.K.
      • Won H.
      • et al.
      Identification of common genetic risk variants for autism spectrum disorder.
      ,
      • Wray N.R.
      • Ripke S.
      • Mattheisen M.
      • Trzaskowski M.
      • Byrne E.M.
      • Abdellaoui A.
      • et al.
      Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.
      ). Despite these similar genetic correlations, we do not see evidence of overtransmission of PRS or case-control differences for these other disorders in our study. It is possible that genetic correlations estimated in previous studies have been overestimated, for example by inclusion of comorbid cases in discovery GWASs (e.g., individuals with both ADHD and MDD in GWASs of each disorder) or through use of overscreened control subjects (
      • Kendler K.S.
      • Chatzinakos C.
      • Bacanu S.A.
      The impact on estimations of genetic correlations by the use of super-normal, unscreened, and family-history screened controls in genome wide case–control studies.
      ). It is also likely that differences in genetic architecture across phenotypes (e.g., smaller total contribution of common variants to heritability for MDD and other disorders) affected these results and that larger sample sizes are needed to detect shared genetic effects. Alternatively, it could be that probands with ADHD who overinherit polygenic liability for both ADHD and other disorders from their parents may show a different phenotype (e.g., ADHD and comorbid BD or psychosis) and meet study exclusion criteria or are less likely to take part in genetic studies and were thus missing from our sample. The replicated undertransmission of OCD PRSs is consistent with recently reported negative genetic correlations (rg [SE] = −0.17 [0.07]) between ADHD and OCD (
      • Yang Z.
      • Wu H.
      • Lee P.H.
      • Tsetsos F.
      • Davis L.K.
      • Yu D.
      • et al.
      Investigating shared genetic basis across Tourette syndrome and comorbid neurodevelopmental disorders along the impulsivity-compulsivity spectrum.
      ) and needs further consideration in future studies. It is possible that probands with a comorbid presentation of ADHD and OCD were less likely to have been included as trios in the current study. This possibility is supported by the slightly higher observed OCD PRSs in the incomplete trios, albeit this result did not survive correction for multiple testing. It has also been suggested that ADHD and OCD represent opposite extremes of the impulsivity-compulsivity continuum, which could explain the opposite directions of genetic effects (
      • Yang Z.
      • Wu H.
      • Lee P.H.
      • Tsetsos F.
      • Davis L.K.
      • Yu D.
      • et al.
      Investigating shared genetic basis across Tourette syndrome and comorbid neurodevelopmental disorders along the impulsivity-compulsivity spectrum.
      ).
      Contrary to the second hypothesis we tested, we found no evidence in either sample of elevated polygenic liability for ADHD in the nontransmitted parental alleles, compared with a control population. Similarly, the results of our exploratory analyses indicated no enrichment of nontransmitted parental alleles for polygenic liability for other neurodevelopmental/psychiatric disorders or for lower cognitive ability. These results are consistent with a recent study and also a preprint, which examined ADHD symptoms in the general population (
      • de Zeeuw E.L.
      • Hottenga J.J.
      • Ouwens K.G.
      • Dolan C.V.
      • Ehli E.A.
      • Davies G.E.
      • et al.
      Intergenerational transmission of education and ADHD: Effects of parental genotypes.
      ,
      • Pingault J.B.
      • Barkhuizen W.
      • Wang B.
      • Hannigan L.J.
      • Eilertsen E.M.
      • Andreassen O.A.
      • et al.
      Identifying intergenerational risk factors for ADHD symptoms using polygenic scores in the Norwegian Mother, Father and Child Cohort.
      ). Our study is different because it focuses on clinical ADHD diagnosis. These studies found that the nontransmitted parental alleles for ADHD and educational attainment do not contribute to risk of ADHD symptoms in a general childhood population, in contrast to transmitted parental alleles (
      • de Zeeuw E.L.
      • Hottenga J.J.
      • Ouwens K.G.
      • Dolan C.V.
      • Ehli E.A.
      • Davies G.E.
      • et al.
      Intergenerational transmission of education and ADHD: Effects of parental genotypes.
      ,
      • Pingault J.B.
      • Barkhuizen W.
      • Wang B.
      • Hannigan L.J.
      • Eilertsen E.M.
      • Andreassen O.A.
      • et al.
      Identifying intergenerational risk factors for ADHD symptoms using polygenic scores in the Norwegian Mother, Father and Child Cohort.
      ). Together with our results and the limited role of shared environmental risks in ADHD reported in twin studies (
      • Faraone S.V.
      • Larsson H.
      Genetics of attention deficit hyperactivity disorder.
      ), this indicates that parental polygenic liability for ADHD primarily impacts on child ADHD risk via direct genetic transmission, rather than indirect genetic nurture effects.
      Our results also indicate that common variant discovery GWASs of ADHD may not be adversely affected by the use of pseudo-control subjects from trios relative to case-control samples, as has been previously suggested (
      • Peyrot W.J.
      • Boomsma D.I.
      • Penninx B.W.J.H.
      • Wray N.R.
      Disease and polygenic architecture: Avoid trio design and appropriately account for unscreened control subjects for common disease.
      ). It is likely that nontransmitted parental risk alleles could be enriched in a subgroup (e.g., families with multiple affected children) or that our use of an unscreened population sample (making this a conservative test) affected the results. This needs to be investigated in future studies. Future studies should also consider the possible effect of comorbid neurodevelopmental/psychiatric symptoms when examining whether nontransmitted risks for other neurodevelopmental/psychiatric phenotypes are enriched in children with ADHD.
      Comparison of polygenic liability in complete and incomplete trios indicated weak differences; probands from incomplete trios had elevated PRSs for BD and OCD and their mothers had elevated ADHD PRSs but decreased schizophrenia PRSs. However, these results did not withstand multiple testing correction and require follow-up using larger samples. We were not able to replicate these analyses because incomplete trios were screened out of the IMAGE cohort. There were no differences in family history of ADHD and other disorders. These results indicate that there are no substantial genetic differences (in terms of PRSs or family history) in probands and their mothers depending on whether they were recruited to the study as part of a complete trio or not. As such, ADHD trio samples are reasonably representative of clinical ADHD samples in terms of polygenic background and our results examining polygenic overtransmission and nontransmitted parental alleles reflect typical UK clinical populations.
      We observed several demographic and clinical differences depending on trio status. Building on a previous study using a subset of 241 (28%) probands drawn from the current sample (
      • West A.
      • Langley K.
      • Hamshere M.L.
      • Kent L.
      • Craddock N.
      • Owen M.J.
      • et al.
      Evidence to suggest biased phenotypes in children with attention deficit hyperactivity disorder from completely ascertained trios.
      ), we observed that probands from incomplete trios had a more severe clinical profile, with more hyperactive-impulsive ADHD and CD symptoms and lower IQ. Probands from incomplete trios were more likely to meet diagnostic criteria for CD, as previously reported (
      • West A.
      • Langley K.
      • Hamshere M.L.
      • Kent L.
      • Craddock N.
      • Owen M.J.
      • et al.
      Evidence to suggest biased phenotypes in children with attention deficit hyperactivity disorder from completely ascertained trios.
      ). We found no differences in inattentive symptoms, ADHD impairment, or symptoms of oppositional defiant disorder, anxiety, or depression. Thus, the group of probands from incomplete trios were not generally more impaired but rather showed specific differences in clinical profile, relating to cognitive ability and behavioral symptoms. However, we note that some of these group differences showed only small effect sizes. We also found differences in socioeconomic variables, which may be explained by the lower SES of single-parent families (
      Child Poverty Action Group
      Child Poverty Facts and Figures, 2021..
      ), who constitute a subset of the incomplete trios. We defined trio status based on availability of DNA from both biological parents, compared with the previous definition of whether fathers of probands with ADHD live with the family and take part in research (
      • West A.
      • Langley K.
      • Hamshere M.L.
      • Kent L.
      • Craddock N.
      • Owen M.J.
      • et al.
      Evidence to suggest biased phenotypes in children with attention deficit hyperactivity disorder from completely ascertained trios.
      ). Although these definitions will overlap, our study is more specifically relevant to considerations of whether trio samples in genetic studies are representative of an ADHD clinical sample and our results indicate that this is not entirely the case.
      Our primary target sample was relatively small, which limited our power to detect smaller effects, particularly for indirect genetic effects, which are likely to be smaller for ADHD than the direct genetic effects. However, we can be more confident in the results owing to our use of a comparable replication sample. One limitation of the replication analysis is that we used the same control individuals as in the primary analysis of nontransmitted alleles, which may have influenced the similarity of these results. We were unable to compare fathers’ polygenic profiles given few fathers in incomplete trios. We were also unable to compare nontransmitted parental alleles for MDD and BD with the control population, owing to the inclusion of the control subjects in those discovery GWASs. Although we found only weak evidence of differences in polygenic liability in complete and incomplete trios, this may have affected the analysis of nontransmitted parental alleles, which needs to be studied further.
      Overall, our results suggest that probands with ADHD overinherit polygenic liability not just for ADHD but also for lower cognitive ability. We found no evidence of enrichment of polygenic liability for neurodevelopmental or psychiatric phenotypes in nontransmitted parental alleles, suggesting that genetically influenced nurture (as captured by the PRSs we tested) does not contribute to ADHD risk. Finally, our results indicate that probands who are recruited to trio-based genetic study designs may not be entirely representative of clinical samples, showing a somewhat less severe clinical profile and higher family SES.

      Acknowledgments and Disclosures

      The work was supported by funding from the Wellcome Trust (Grant Nos. 079711 and 220488/Z/20/Z), Medical Research Council Centre (Grant No. MR/L010305/1), Health and Care Research Wales (Grant No. 514032), Action Medical Research , and Baily Thomas. We also acknowledge the support of the Supercomputing Wales project, which is part-funded by the European Regional Development Fund ( ERDF ) via Welsh Government . JM was supported by a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (Grant No. 27879). This work was supported by the Wolfson Centre for Young People’s Mental Health. This research was funded in whole, or in part, by the Wellcome Trust .
      For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
      Funding support for the IMAGE project was provided by National Institutes of Health (Grant Nos. R01MH62873 and R01MH081803 to S.V. Faraone) and the genotyping of samples was provided through the Genetic Association Information Network.
      Study conception & design: JM, KL; Data preparation and analysis: JM, MW, KL, RJLA; Writing (original draft): JM, MW; Writing (review & editing): All authors.
      We acknowledge dbGaP, via the dbGaP accession: phs000016.v2.p2 https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000016.v2.p2. The dataset(s) used for the analyses described in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) available at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession No. 26394. Samples and associated phenotype data for the International Multi-Center ADHD Genetics Project were provided by the following investigators: S. Faraone (principal investigator), R. Anney, P. Asherson, J. Sergeant, R. Ebstein, B. Franke, M. Gill, A. Miranda, F. Mulas, R. Oades, H. Roeyers, A. Rothenberger, T. Banaschewski, J. Buitelaar, E. Sonuga-Barke (site principal investigators), M. Daly, C. Lange, N. Laird, J. Su, and B. Neale (statistical analysis team).
      The authors report no biomedical financial interests or potential conflicts of interest.

      Supplementary Material

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