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

Gene-set and multivariate genome-wide association analysis of oppositional defiant behavior subtypes in attention-deficit/hyperactivity disorder
Gene-set and multivariate genome-wide association analysis of oppositional defiant behavior subtypes in attention-deficit/hyperactivity disorder
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 antecedent 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.
ODD, GWAS, irritability, ?-catenin, neurite outgrowth
1552-4841
1-16
Aebi, Marcel
774f8243-1454-46c9-8618-092f68fa1d93
van Donkelaar, Marjolein M.J.
dcc01534-1731-4b2b-b0ac-d154b27a5611
Poelmans, Geert
80351746-1298-4dbb-b736-b955515dc4c7
Buitelaar, Jan K.
a2e08a14-4de4-419e-9ea8-1e97ebbdddba
Sonuga-Barke, Edmund J.S.
bc80bf95-6cf9-4c76-a09d-eaaf0b717635
Stringaris, Argyris
b813012e-7b67-432b-9799-2187bf675c30
consortium, IMAGE
b3134582-e657-4665-8c9c-5dd7ff0a461c
Faraone, Stephen V.
bd307516-e8db-4d38-b649-9d7d7caafe93
Franke, Barbara
f71c8989-a108-40c4-a159-80a1e60b56bf
Steinhausen, Hans-Christoph
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van Hulzen, Kimm J. E.
bdcb7a27-9914-415c-9d8d-a4d91bfb1fde
Aebi, Marcel
774f8243-1454-46c9-8618-092f68fa1d93
van Donkelaar, Marjolein M.J.
dcc01534-1731-4b2b-b0ac-d154b27a5611
Poelmans, Geert
80351746-1298-4dbb-b736-b955515dc4c7
Buitelaar, Jan K.
a2e08a14-4de4-419e-9ea8-1e97ebbdddba
Sonuga-Barke, Edmund J.S.
bc80bf95-6cf9-4c76-a09d-eaaf0b717635
Stringaris, Argyris
b813012e-7b67-432b-9799-2187bf675c30
consortium, IMAGE
b3134582-e657-4665-8c9c-5dd7ff0a461c
Faraone, Stephen V.
bd307516-e8db-4d38-b649-9d7d7caafe93
Franke, Barbara
f71c8989-a108-40c4-a159-80a1e60b56bf
Steinhausen, Hans-Christoph
991ad7f9-c5d1-4c61-8118-3d4895d2706d
van Hulzen, Kimm J. E.
bdcb7a27-9914-415c-9d8d-a4d91bfb1fde

Aebi, Marcel, van Donkelaar, Marjolein M.J., Poelmans, Geert, Buitelaar, Jan K., Sonuga-Barke, Edmund J.S., Stringaris, Argyris, consortium, IMAGE, Faraone, Stephen V., Franke, Barbara, Steinhausen, Hans-Christoph and van Hulzen, Kimm J. E. (2015) 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, 1-16. (doi:10.1002/ajmg.b.32346). (PMID:26184070)

Record type: Article

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 antecedent 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.

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More information

Accepted/In Press date: 29 June 2015
e-pub ahead of print date: 16 July 2015
Published date: 16 July 2015
Keywords: ODD, GWAS, irritability, ?-catenin, neurite outgrowth
Organisations: Clinical Neuroscience

Identifiers

Local EPrints ID: 379554
URI: http://eprints.soton.ac.uk/id/eprint/379554
ISSN: 1552-4841
PURE UUID: 0f7ab0a6-244e-4064-8269-fc22d55bba91

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Date deposited: 05 Aug 2015 14:37
Last modified: 25 Sep 2018 16:31

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Contributors

Author: Marcel Aebi
Author: Marjolein M.J. van Donkelaar
Author: Geert Poelmans
Author: Jan K. Buitelaar
Author: Edmund J.S. Sonuga-Barke
Author: Argyris Stringaris
Author: IMAGE consortium
Author: Stephen V. Faraone
Author: Barbara Franke
Author: Hans-Christoph Steinhausen
Author: Kimm J. E. van Hulzen

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