Identification of risk variants and characterization of the polygenic architecture of disruptive behavior disorders in the context of ADHD

Demontis, Ditte; Walters, Raymond; Rajagopal, Veera; Waldman, Irwin D.; Grove, Jakob; Als, Thomas Damm; Dalsgaard, Søren; Ribasés, Marta; Grauholm, Jonas; Bækvad‐Hansen, Marie; Werge, Thomas; Nordentoft, Merete; Mors, Ole; Mortensen, Preben Bo; Cormand, Bru; Hougaard, David M.; Neale, Benjamin M.; Franke, Barbara; Faraone, Stephen V.; Børglum, Anders D.

doi:10.1101/791160

Cited by 3 publications

(3 citation statements)

References 85 publications

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“…Interestingly, ADHD was not genetically correlated with antisocial behavior in another study, likely due to the relatively small sample size and the heterogeneity of measures of antisocial behavior 121 . In contrast, ODD or CD in the context of ADHD was highly genetically correlated with aggression and antisocial behavior, and its polygenic risk score was more predictive of cognitive functioning, educational outcomes, and having children at a younger age than that for ADHD without ODD or CD 120 . Nonetheless, the maximum variance explained by the polygenic risk score in these outcomes was quite low (0.36%).…”

Section: Validity Evidencementioning

confidence: 92%

“…Genomewide association studies (GWAS) of various child hood disorders, such as ADHD 118 , CD 119 , and ODD or CD within the context of ADHD 120 , have found evidence for several genome wide significant associations and polygenic influences, each with a small effect size, that contribute to the risk for these disorders. In addition, moderate genetic correlations have been found be tween ADHD and other disorders, such as depression and ano rexia nervosa; related traits, such as neuroticism and subjective wellbeing (negative); and important life outcomes, including ever having smoked, the number of cigarettes smoked per day, and intelligence and educational attainment (both negative) 120 . Interestingly, ADHD was not genetically correlated with anti social behavior in another study, likely due to the relatively small sample size and the heterogeneity of measures of antisocial be havior 121 .…”

Section: Molecular Genetic Evidencementioning

confidence: 99%

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Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): II. Externalizing superspectrum

et al. 2021

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The Hierarchical Taxonomy of Psychopathology (HiTOP) is an empirical effort to address limitations of traditional mental disorder diagnoses. These include arbitrary boundaries between disorder and normality, disorder co‐occurrence in the modal case, heterogeneity of presentation within disorders, and instability of diagnosis within patients. This paper reviews the evidence on the validity and utility of the disinhibited externalizing and antagonistic externalizing spectra of HiTOP, which together constitute a broad externalizing superspectrum. These spectra are composed of elements subsumed within a variety of mental disorders described in recent DSM nosologies, including most notably substance use disorders and “Cluster B” personality disorders. The externalizing superspectrum ranges from normative levels of impulse control and self‐assertion, to maladaptive disinhibition and antagonism, to extensive polysubstance involvement and personality psychopathology. A rich literature supports the validity of the externalizing superspectrum, and the disinhibited and antagonistic spectra. This evidence encompasses common genetic influences, environmental risk factors, childhood antecedents, cognitive abnormalities, neural alterations, and treatment response. The structure of these validators mirrors the structure of the phenotypic externalizing superspectrum, with some correlates more specific to disinhibited or antagonistic spectra, and others relevant to the entire externalizing superspectrum, underlining the hierarchical structure of the domain. Compared with traditional diagnostic categories, the externalizing superspectrum conceptualization shows improved utility, reliability, explanatory capacity, and clinical applicability. The externalizing superspectrum is one aspect of the general approach to psychopathology offered by HiTOP and can make diagnostic classification more useful in both research and the clinic.

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Section: Validity Evidencementioning

confidence: 92%

Section: Molecular Genetic Evidencementioning

confidence: 99%

Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): II. Externalizing superspectrum

et al. 2021

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“…Other genes such as Mastermind Like Transcriptional Coactivator 3 (MAML3; chromosomal 4 at 4q28.3) and the DRD5 dopamine D5 receptor (DRD5; chromosome 4 at 4p15.3) have been explored as potential contributors to ADHD and disruptive behavioral disturbances [19,20]. Although their role in the presentation of chromosome 4q deletion is not well understood.…”

Section: Discussionmentioning

confidence: 99%

A Novel Psychiatric Phenotype of Chromosome 4q Deletion: A case report

Vaithilingam,

Garrison,

Krantz

et al. 2023

Preprint

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Background Chromosome 4q deletion is a rare genetic disorder affecting an estimated 1 out of 100,000 people, although there are relatively few reports in the literature. It is characterized by microdeletions of the long arm of chromosome 4 with variable clinical presentations including heart defects, craniofacial and skeletal abnormalities, short stature, and developmental delays. While behavioral and psychiatric symptoms have been reported in a small number of Chromosome 4q deletion patients, none of these reports have described the hyperphagia or parasomnia symptoms that are presented in the current case.Case presentation A 7-year-old male patient presented with a microdeletion of the long arm of chromosome 4 that resulted in psychiatric symptoms and neurodevelopmental delays. Notable manifestations included aggression, hyperphagia, parasomnias, functional encopresis and speech delays. At inpatient admission, a multidisciplinary approach to diagnosis and treatment was adopted, encompassing pharmacological and behavioral interventions. His initial treatment was markedly delayed due to limited genetic testing at age one, which led to a misdiagnosis of childhood aggression. This limited the care team involvement for neurologic evaluation and appropriate school interventions that would have otherwise been indicated.Conclusion Chromosome 4q deletion -related behaviors parallel that of children with autism spectrum disorder (ASD), and treatment is primarily focused on behavioral interventions. In the current case, the patient’s attention-deficit/hyperactivity disorder (ADHD) was treated, and his individualized education plan (IEP) recommendations included a functional behavioral assessment, the Behavioral Assessment System for Children, occupational therapy services and speech and language services. Following a 4-day inpatient stay, the patient demonstrated a significant decrease in aggressive behaviors.

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Systematic Review: Molecular Studies of Common Genetic Variation in Child and Adolescent Psychiatric Disorders

Akingbuwa

Hammerschlag

Bartels

et al. 2022

Journal of the American Academy of Child & Adolescent Psych

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Objective: A systematic review of studies using molecular genetics and statistical approaches to investigate the role of common genetic variation in the development, persistence, and comorbidity of childhood psychiatric traits was conducted. Method: A literature review was performed using the PubMed database, following the Preferred Reporting Items for Meta-Analyses guidelines. There were 131 studies meeting inclusion criteria, having investigated at least one type of childhood-onset or childhood-measured psychiatric disorder or trait with the aim of identifying trait-associated common genetic variants, estimating the contribution of single nucleotide polymorphisms to the amount of variance explained (single nucleotide polymorphism heritability), investigating genetic overlap between psychiatric traits, or investigating whether the stability in traits or the association with adult traits is explained by genetic factors. Results: The first robustly associated genetic variants have started to be identified for childhood psychiatric traits. There were substantial contributions of common genetic variants to many traits, with variation in single nucleotide polymorphism heritability estimates depending on age and raters. Moreover, genetic variants also appeared to explain comorbidity as well as stability across a range of psychiatric traits in childhood and across the life span. Conclusion: Common genetic variation plays a substantial role in childhood psychiatric traits. Increased sample sizes will lead to increased power to identify genetic variants and to understand genetic architecture, which will ultimately be beneficial to targeted and prevention strategies. This can be achieved by harmonizing phenotype measurements, as is already proposed by large international consortia and by including the collection of genetic material in every study.

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Identification of risk variants and characterization of the polygenic architecture of disruptive behavior disorders in the context of ADHD

Cited by 3 publications

References 85 publications

Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): II. Externalizing superspectrum

Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): II. Externalizing superspectrum

A Novel Psychiatric Phenotype of Chromosome 4q Deletion: A case report

Systematic Review: Molecular Studies of Common Genetic Variation in Child and Adolescent Psychiatric Disorders

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