Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Demontis, Ditte; Walters, Raymond; Martin, Joanna; Mattheisen, Manuel; Als, Thomas Damm; Agerbo, Esben; Baldursson, Gísli; Belliveau, Rich; Bybjerg‐Grauholm, Jonas; Bækvad‐Hansen, Marie; Cerrato, Felecia; Chambert, Kimberly; Churchhouse, Claire; DuMont, Ashley L.; Eriksson, Nicholas; Gandal, Michael J.; Goldstein, Jacqueline I.; Grasby, Katrina L.; Grove, Jakob; Guðmundsson, Ólafur Ó.; Hansen, Christine Søholm; Hauberg, Mads E.; Hollegaard, Mads V.; Howrigan, Daniel P.; Huang, Hailiang; Maller, Julian; Martin, Alicia R.; Martin, Nicholas G.; Moran, Jennifer L.; Pallesen, Jonatan; Palmer, Duncan S.; Pedersen, Carsten Bøcker; Pedersen, Marianne Giørtz; Poterba, Timothy; Poulsen, Jesper Buchhave; Ripke, Stephan; Robinson, Elise; Satterstrom, F. Kyle; Stefánsson, Hreinn; Stevens, Christine; Turley, Patrick; Walters, G. Bragi; Won, Hyejung; Wright, Margaret J.; Andreassen, Ole A.; Asherson, Philip; Burton, Christie L.; Boomsma, Dorret I.; Cormand, Bru; Dalsgaard, Søren; Franke, Barbara; Gelernter, Joel; Geschwind, Daniel H.; Hákonarson, Hákon; Haavik, Jan; Kranzler, Henry R.; Kuntsi, Jonna; Langley, Kate; Lesch, Klaus‐Peter; Middeldorp, Christel M.; Reif, Andreas; Rohde, Luís Augusto; Roussos, Panos; Schachar, Russell; Sklar, Pamela; Sonuga‐Barke, Edmund; Sullivan, Patrick F.; Thapar, Anita; Tung, Joyce Y.; Waldman, Irwin D.; Medland, Sarah E.; Stefánsson, Kāri; Nordentoft, Merete; Hougaard, David M.; Werge, Thomas; Mors, Ole; Mortensen, Preben Bo; Daly, Mark J.; Faraone, Stephen V.; Børglum, Anders D.; Neale, Benjamin M.

doi:10.1038/s41588-018-0269-7

Cited by 1,840 publications

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“…Furthermore, it is important to be aware of potential factors that can influence the PGSs. In Grove et al's ASD sample it is likely that some of the participants might have had comorbid ADHD [Grove et al, ], and the ADHD risk score calculated by Demontis et al might be more specific to ADHD [Demontis et al, ]. However, it is likely that there is some overlap between all the different phenotypes, especially at P ‐values as high as 0.1.…”

Section: Discussionmentioning

confidence: 99%

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Autism spectrum disorder polygenic scores are associated with every day executive function in children admitted for clinical assessment

et al. 2019

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Autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDs) are behaviorally defined disorders with overlapping clinical features that are often associated with higher‐order cognitive dysfunction, particularly executive dysfunction. Our aim was to determine if the polygenic score (PGS) for ASD is associated with parent‐reported executive dysfunction in everyday life using the Behavior Rating Inventory of Executive Function (BRIEF). Furthermore, we investigated if PGS for general intelligence (INT) and attention deficit/hyperactivity disorder (ADHD) also correlate with BRIEF. We included 176 children, adolescents and young adults aged 5–22 years with full‐scale intelligence quotient (IQ) above 70. All were admitted for clinical assessment of ASD symptoms and 68% obtained an ASD diagnosis. We found a significant difference between low and high ASD PGS groups in the BRIEF behavior regulation index (BRI) (P = 0.015, Cohen's d = 0.69). A linear regression model accounting for age, sex, full‐scale IQ, Social Responsiveness Scale (SRS) total score, ASD, ADHD and INT PGS groups as well as genetic principal components, significantly predicted the BRI score; F(11,130) = 8.142, P < 0.001, R2 = 0.41 (unadjusted). Only SRS total (P < 0.001), ASD PGS 0.1 group (P = 0.018), and sex (P = 0.022) made a significant contribution to the model. This suggests that the common ASD risk gene variants have a stronger association to behavioral regulation aspects of executive dysfunction than ADHD risk or INT variants in a clinical sample with ASD symptoms. Autism Res 2020, 13: 207–220. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary People with autism spectrum disorder (ASD) often have difficulties with higher‐order cognitive processes that regulate thoughts and actions during goal‐directed behavior, also known as executive function (EF). We studied the association between genetics related to ASD and EF and found a relation between high polygenic score (PGS) for ASD and difficulties with behavior regulation aspects of EF in children and adolescents under assessment for ASD. Furthermore, high PGS for general intelligence was related to social problems.

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Section: Discussionmentioning

confidence: 99%

“…In the linear regression, we used the groups Low, Moderate and High PGSs. The discovery samples our PGS are based on consisted of 18,381 ASD cases and 27,969 controls for the ASD PGS [Grove et al, ], 20,183 ADHD cases and 35,191 controls for the ADHD PGS [Demontis et al, ] and 269,867 cases for the INT PGS [Savage et al, ].…”

Section: Methodsmentioning

confidence: 99%

Autism spectrum disorder polygenic scores are associated with every day executive function in children admitted for clinical assessment

et al. 2019

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“…We also obtained the first PC from polygenic scores for psychiatric disorders (polygenic p). We used publicly available genome‐wide association summary statistics for eight major psychiatric traits: autism spectrum disorder (Grove et al., ), major depressive disorder (MDD; Wray et al., ), bipolar disorder (BIP), schizophrenia (SCZ; Pardiñas et al., ), attention deficit hyperactivity disorder (ADHD; Demontis et al., ), obsessive–compulsive disorder (OCD; International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF‐GC) and OCD Collaborative Genetics Association Studies (OCGAS), ), anorexia nervosa (AN; Duncan et al., ) and posttraumatic stress disorder (PTSD; Duncan et al., ). For each psychiatric disorder, polygenic scores for each TEDS participant were created in LDpred (Vilhjálmsson et al., ), assuming a fraction of causal markers of 1 (analysis steps were similar to Selzam et al., ).…”

Section: Methodsmentioning

confidence: 99%

The p factor: genetic analyses support a general dimension of psychopathology in childhood and adolescence

Allegrini

Cheesman

Rimfeld

et al. 2019

Child Psychology Psychiatry

159

146

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Background Diverse behaviour problems in childhood correlate phenotypically, suggesting a general dimension of psychopathology that has been called the p factor. The shared genetic architecture between childhood psychopathology traits also supports a genetic p. This study systematically investigates the manifestation of this common dimension across self‐, parent‐ and teacher‐rated measures in childhood and adolescence. Methods The sample included 7,026 twin pairs from the Twins Early Development Study (TEDS). First, we employed multivariate twin models to estimate common genetic and environmental influences on p based on diverse measures of behaviour problems rated by children, parents and teachers at ages 7, 9, 12 and 16 (depressive traits, emotional problems, peer problems, autism traits, hyperactivity, antisocial behaviour, conduct problems and psychopathic tendencies). Second, to assess the stability of genetic and environmental influences on p across time, we conducted longitudinal twin modelling of the first phenotypic principal components of childhood psychopathological measures across each of the four ages. Third, we created a genetic p factor in 7,026 unrelated genotyped individuals based on eight polygenic scores for psychiatric disorders to estimate how a general polygenic predisposition to mostly adult psychiatric disorders relates to childhood p. Results Behaviour problems were consistently correlated phenotypically and genetically across ages and raters. The p factor is substantially heritable (50%–60%) and manifests consistently across diverse ages and raters. However, residual variation in the common factor models indicates unique contributions as well. Genetic correlations of p components across childhood and adolescence suggest stability over time (49%–78%). A polygenic general psychopathology factor derived from studies of psychiatric disorders consistently predicted a general phenotypic p factor across development (0.3%–0.9%). Conclusions Diverse forms of psychopathology generally load on a common p factor, which is highly heritable. There are substantial genetic influences on the stability of p across childhood. Our analyses indicate genetic overlap between general risk for psychiatric disorders in adulthood and p in childhood, even as young as age 7. The p factor has far‐reaching implications for genomic research and, eventually, for diagnosis and treatment of behaviour problems.

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“…Finally, the study on ADHD ( N cases = 20,183, N controls = 35,191) included 12 cohorts from Europe, North America, and China. Cases had a clinical diagnosis of ADHD (ADHD Working Group of the Psychiatric Genomics Consortium (PGC) et al, ).…”

Section: Methodsmentioning

confidence: 99%

Genome‐Wide Association Study of Latent Cognitive Measures in Adolescence: Genetic Overlap With Intelligence and Education

Donati

Dumontheil

Meaburn

2019

Mind Brain and Education

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Individual differences in executive functions (EF) are heritable and predictive of academic attainment (AA). However, little is known about genetic contributions to EFs or their genetic relationship with AA and intelligence. We conducted genome‐wide association analyses for processing speed (PS) and the latent EF measures of working memory (WM) and inhibitory control (IC) in 4,611 adolescents from the Avon Longitudinal Study of Parents and Children. While no loci reached genome‐wide significance, common genetic variants explained 30% of the variance in WM and 19% in PS. In contrast, we failed to find common genetic contributions to IC. Finally, we examined shared genetic effects between EFs and general intelligence, AA and ADHD. We identified significant genetic correlations between WM, intelligence, and AA. A more specific pattern was observed for PS, with modest genetic overlap with intelligence. Together these findings highlight diversity in the genetic contributions to specific cognitive functions and their genetic relationship with educational and psychiatric outcomes.

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Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Cited by 1,840 publications

References 137 publications

Autism spectrum disorder polygenic scores are associated with every day executive function in children admitted for clinical assessment

Autism spectrum disorder polygenic scores are associated with every day executive function in children admitted for clinical assessment

The p factor: genetic analyses support a general dimension of psychopathology in childhood and adolescence

Genome‐Wide Association Study of Latent Cognitive Measures in Adolescence: Genetic Overlap With Intelligence and Education

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