CONTEXT: As genes associated with common disorders are increasingly identified, we need to progress from observing associations to identifying risk pathways. The high-activity COMT genotype, in the presence of attention-deficit/hyperactivity disorder (ADHD), has previously been shown to be associated with extreme antisocial behavior. The same genotype has also been implicated in affecting cognitive function in healthy individuals. Impaired cognitive function might therefore lie on the risk pathway from genotype to clinical outcome. OBJECTIVES: To replicate the association between COMT genotype and antisocial behavior in ADHD and to then test whether (1) impaired executive control or (2) impaired social understanding act as intermediate phenotypes for this association and lie on the risk pathway between COMT genotype and antisocial behavior. DESIGN: Prospective epidemiological cohort sample. SETTING: The Avon Longitudinal Study of Parents and Children. PARTICIPANTS: Four thousand three hundred sixty-five children with data on COMT Val¹⁵⁸Met genotype, ADHD symptoms and diagnoses, and measures of social cognition/understanding and executive control. MAIN OUTCOME MEASURES: Antisocial behavior at age 7.5 years assessed using DSM-IV conduct disorder symptoms. RESULTS: We replicated the association of the high-activity COMT genotype, in the presence of ADHD, with extreme antisocial behavior (odds ratio, 2.82; 95% confidence interval, 2.02-3.94; P < .001 for the most severe antisocial behavior). The high-activity COMT genotype was associated with both executive control and impaired social understanding. The strength of the association between genotype and antisocial behavior was unchanged by including executive control in the model but dropped when impaired social understanding was included (odds ratio, 1.87; 95% confidence interval, 1.26-2.76; P = .002). CONCLUSIONS: The high-activity COMT genotype in ADHD is associated with antisocial behavior in part via impaired social understanding. Impaired executive control was also associated with the high-activity COMT genotype but may not lie on the risk pathway to antisocial behavior. The findings demonstrate the importance of testing links between genotype, intermediate phenotype, and clinical outcome in the same sample to identify potential risk pathways.
CONTEXT: As genes associated with common disorders are increasingly identified, we need to progress from observing associations to identifying risk pathways. The high-activity COMT genotype, in the presence of attention-deficit/hyperactivity disorder (ADHD), has previously been shown to be associated with extreme antisocial behavior. The same genotype has also been implicated in affecting cognitive function in healthy individuals. Impaired cognitive function might therefore lie on the risk pathway from genotype to clinical outcome. OBJECTIVES: To replicate the association between COMT genotype and antisocial behavior in ADHD and to then test whether (1) impaired executive control or (2) impaired social understanding act as intermediate phenotypes for this association and lie on the risk pathway between COMT genotype and antisocial behavior. DESIGN: Prospective epidemiological cohort sample. SETTING: The Avon Longitudinal Study of Parents and Children. PARTICIPANTS: Four thousand three hundred sixty-five children with data on COMT Val¹⁵⁸Met genotype, ADHD symptoms and diagnoses, and measures of social cognition/understanding and executive control. MAIN OUTCOME MEASURES: Antisocial behavior at age 7.5 years assessed using DSM-IV conduct disorder symptoms. RESULTS: We replicated the association of the high-activity COMT genotype, in the presence of ADHD, with extreme antisocial behavior (odds ratio, 2.82; 95% confidence interval, 2.02-3.94; P < .001 for the most severe antisocial behavior). The high-activity COMT genotype was associated with both executive control and impaired social understanding. The strength of the association between genotype and antisocial behavior was unchanged by including executive control in the model but dropped when impaired social understanding was included (odds ratio, 1.87; 95% confidence interval, 1.26-2.76; P = .002). CONCLUSIONS: The high-activity COMT genotype in ADHD is associated with antisocial behavior in part via impaired social understanding. Impaired executive control was also associated with the high-activity COMT genotype but may not lie on the risk pathway to antisocial behavior. The findings demonstrate the importance of testing links between genotype, intermediate phenotype, and clinical outcome in the same sample to identify potential risk pathways.
Authors: Angélica Salatino-Oliveira; Julia P Genro; Ana P Guimarães; Rodrigo Chazan; Cristian Zeni; Marcelo Schmitz; Guilherme Polanczyk; Tatiana Roman; Luis A Rohde; Mara H Hutz Journal: J Neural Transm (Vienna) Date: 2012-01-21 Impact factor: 3.575
Authors: Glaucia C Akutagava-Martins; Angelica Salatino-Oliveira; Christian Kieling; Julia P Genro; Guilherme V Polanczyk; Luciana Anselmi; Ana M B Menezes; Helen Gonçalves; Fernando C Wehrmeister; Fernando C Barros; Sidia M Callegari-Jacques; Luis A Rohde; Mara H Hutz Journal: J Psychiatry Neurosci Date: 2016-10 Impact factor: 6.186
Authors: Kent W Nilsson; Karin Sonnby; Niklas Nordquist; Erika Comasco; Jerzy Leppert; Lars Oreland; Rickard L Sjöberg Journal: Eur Child Adolesc Psychiatry Date: 2013-07-04 Impact factor: 4.785
Authors: B Franke; S V Faraone; P Asherson; J Buitelaar; C H D Bau; J A Ramos-Quiroga; E Mick; E H Grevet; S Johansson; J Haavik; K-P Lesch; B Cormand; A Reif Journal: Mol Psychiatry Date: 2011-11-22 Impact factor: 15.992
Authors: Natasha Matthews; Alasdair Vance; Tarrant D R Cummins; Joseph Wagner; Amanda Connolly; Jacqueline Yamada; Paul J Lockhart; Ajay Panwar; Robyn H Wallace; Mark A Bellgrove Journal: Behav Brain Funct Date: 2012-05-28 Impact factor: 3.759
Authors: Marian L Hamshere; Kate Langley; Joanna Martin; Sharifah Shameem Agha; Evangelia Stergiakouli; Richard J L Anney; Jan Buitelaar; Stephen V Faraone; Klaus-Peter Lesch; Benjamin M Neale; Barbara Franke; Edmund Sonuga-Barke; Philip Asherson; Andrew Merwood; Jonna Kuntsi; Sarah E Medland; Stephan Ripke; Hans-Christoph Steinhausen; Christine Freitag; Andreas Reif; Tobias J Renner; Marcel Romanos; Jasmin Romanos; Andreas Warnke; Jobst Meyer; Haukur Palmason; Alejandro Arias Vasquez; Nanda Lambregts-Rommelse; Herbert Roeyers; Joseph Biederman; Alysa E Doyle; Hakon Hakonarson; Aribert Rothenberger; Tobias Banaschewski; Robert D Oades; James J McGough; Lindsey Kent; Nigel Williams; Michael J Owen; Peter Holmans; Michael C O'Donovan; Anita Thapar Journal: Am J Psychiatry Date: 2013-08 Impact factor: 18.112
Authors: Angélica Salatino-Oliveira; Joseph Murray; Christian Kieling; Júlia Pasqualini Genro; Guilherme Polanczyk; Luciana Anselmi; Fernando Wehrmeister; Fernando C de Barros; Ana Maria Baptista Menezes; Luis Augusto Rohde; Mara Helena Hutz Journal: Sci Rep Date: 2016-07-18 Impact factor: 4.379