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Gene-set and multivariate genome-wide association analysis of oppositional defiant behavior subtypes in attention-deficit/hyperactivity disorder

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Abstract
Oppositional defiant disorder (ODD) is a frequent psychiatric disorder seen in children and adolescents with attention-deficit-hyperactivity disorder (ADHD). ODD is also a common ante-cedent to both affective disorders and aggressive behaviors. Although the heritability of ODD has been estimated to be around 0.60, there has been little research into the molecular genetics of ODD. The present study examined the association of irritable and defiant/vindictive dimensions and categorical subtypes of ODD(based on latent class analyses) with previously described specific polymorphisms (DRD4 exon3 VNTR, 5-HTTLPR, and seven OXTR SNPs) as well as with dopamine, serotonin, and oxytocin genes and pathways in a clinical sample of children and adolescents with ADHD. In addition, we performed a multivariate genome-wide association study (GWAS) of the aforementioned ODD dimensions and subtypes. Apart from adjusting the analyses for age and sex, we controlled for "parental ability to cope with disruptive behavior." None of the hypothesis-driven analyses revealed a significant association with ODD dimensions and subtypes. Inadequate parenting behavior was significantly associated with all ODD dimensions and subtypes, most strongly with defiant/vindictive behaviors. In addition, the GWAS did not result in genome-wide significant findings but bioinformatics and literature analyses revealed that the proteins encoded by 28 of the 53 top-ranked genes functionally interact in a molecular landscape centered around Beta-catenin signaling and involved in the regulation of neurite outgrowth. Our findings provide new insights into the molecular basis of ODD and inform future genetic studies of oppositional behavior. (C) 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
Keywords
DEFICIT HYPERACTIVITY DISORDER, CALLOUS-UNEMOTIONAL TRAITS, CHILD, PSYCHIATRIC-PATIENTS, LARGE MULTICENTER ADHD, CONDUCT DISORDER, AGGRESSIVE-BEHAVIOR, SEROTONIN TRANSPORTER, ANTISOCIAL-BEHAVIOR, DIAGNOSTIC-APPROACH, OXTR POLYMORPHISMS, ODD, GWAS, irritability, beta-catenin, neurite outgrowth

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Citation

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Chicago
Aebi, Marcel, Marjolein MJ van Donkelaar, Geert Poelmans, Jan K Buitelaar, Edmund Barke, Argyris Stringaris, Stephen V Faraone, Barbara Franke, Hans-Christoph Steinhausen, and Kimm JE van Hulzen. 2016. “Gene-set and Multivariate Genome-wide Association Analysis of Oppositional Defiant Behavior Subtypes in Attention-deficit/hyperactivity Disorder.” American Journal of Medical Genetics Part B-neuropsychiatric Genetics 171 (5): 573–588.
APA
Aebi, M., van Donkelaar, M. M., Poelmans, G., Buitelaar, J. K., Barke, E., Stringaris, A., Faraone, S. V., et al. (2016). Gene-set and multivariate genome-wide association analysis of oppositional defiant behavior subtypes in attention-deficit/hyperactivity disorder. AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 171(5), 573–588.
Vancouver
1.
Aebi M, van Donkelaar MM, Poelmans G, Buitelaar JK, Barke E, Stringaris A, et al. Gene-set and multivariate genome-wide association analysis of oppositional defiant behavior subtypes in attention-deficit/hyperactivity disorder. AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS. Hoboken: Wiley-blackwell; 2016;171(5):573–88.
MLA
Aebi, Marcel et al. “Gene-set and Multivariate Genome-wide Association Analysis of Oppositional Defiant Behavior Subtypes in Attention-deficit/hyperactivity Disorder.” AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS 171.5 (2016): 573–588. Print.
@article{8508717,
  abstract     = {Oppositional defiant disorder (ODD) is a frequent psychiatric disorder seen in children and adolescents with attention-deficit-hyperactivity disorder (ADHD). ODD is also a common ante-cedent to both affective disorders and aggressive behaviors. Although the heritability of ODD has been estimated to be around 0.60, there has been little research into the molecular genetics of ODD. The present study examined the association of irritable and defiant/vindictive dimensions and categorical subtypes of ODD(based on latent class analyses) with previously described specific polymorphisms (DRD4 exon3 VNTR, 5-HTTLPR, and seven OXTR SNPs) as well as with dopamine, serotonin, and oxytocin genes and pathways in a clinical sample of children and adolescents with ADHD. In addition, we performed a multivariate genome-wide association study (GWAS) of the aforementioned ODD dimensions and subtypes. Apart from adjusting the analyses for age and sex, we controlled for "parental ability to cope with disruptive behavior." None of the hypothesis-driven analyses revealed a significant association with ODD dimensions and subtypes. Inadequate parenting behavior was significantly associated with all ODD dimensions and subtypes, most strongly with defiant/vindictive behaviors. In addition, the GWAS did not result in genome-wide significant findings but bioinformatics and literature analyses revealed that the proteins encoded by 28 of the 53 top-ranked genes functionally interact in a molecular landscape centered around Beta-catenin signaling and involved in the regulation of neurite outgrowth. Our findings provide new insights into the molecular basis of ODD and inform future genetic studies of oppositional behavior. (C) 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.},
  author       = {Aebi, Marcel and van Donkelaar, Marjolein MJ and Poelmans, Geert and Buitelaar, Jan K and Barke, Edmund and Stringaris, Argyris and Faraone, Stephen V and Franke, Barbara and Steinhausen, Hans-Christoph and van Hulzen, Kimm JE},
  issn         = {1552-4841},
  journal      = {AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS},
  keywords     = {DEFICIT HYPERACTIVITY DISORDER,CALLOUS-UNEMOTIONAL TRAITS,CHILD,PSYCHIATRIC-PATIENTS,LARGE MULTICENTER ADHD,CONDUCT DISORDER,AGGRESSIVE-BEHAVIOR,SEROTONIN TRANSPORTER,ANTISOCIAL-BEHAVIOR,DIAGNOSTIC-APPROACH,OXTR POLYMORPHISMS,ODD,GWAS,irritability,beta-catenin,neurite outgrowth},
  language     = {eng},
  number       = {5},
  pages        = {573--588},
  publisher    = {Wiley-blackwell},
  title        = {Gene-set and multivariate genome-wide association analysis of oppositional defiant behavior subtypes in attention-deficit/hyperactivity disorder},
  url          = {http://dx.doi.org/10.1002/ajmg.b.32346},
  volume       = {171},
  year         = {2016},
}

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