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Andreas Reif, MD; Christian P. Jacob, MD; Dan Rujescu, MD; Sabine Herterich, PhD; Sebastian Lang, MD; Lise Gutknecht, PhD; Christina G. Baehne, Dipl-Psych; Alexander Strobel, PhD; Christine M. Freitag, MD; Ina Giegling, MD; Marcel Romanos, MD; Annette Hartmann, MD; Michael Rösler, MD; Tobias J. Renner, MD; Andreas J. Fallgatter, MD; Wolfgang Retz, MD; Ann-Christine Ehlis, PhD; Klaus-Peter Lesch, MD

Arch Gen Psychiatry. 2009;66(1):41-50.

Context  Human personality is characterized by substantial heritability but few functional gene variants have been identified. Although rodent data suggest that the neuronal isoform of nitric oxide synthase (NOS-I) modifies diverse behaviors including aggression, this has not been translated to human studies.

Objectives  To investigate the functionality of an NOS1 promoter repeat length variation (NOS1 Ex1f variable number tandem repeat [VNTR]) and to test whether it is associated with phenotypes relevant to impulsivity.

Design  Molecular biological studies assessed the cellular consequences of NOS1 Ex1f VNTR; association studies were conducted to investigate the impact of this genetic variant on impulsivity; imaging genetics was applied to determine whether the polymorphism is functional on a neurobiological level.

Setting  Three psychiatric university clinics in Germany.

Participants  More than 3200 subjects were included in the association study: 1954 controls, 403 patients with personality disorder, 383 patients with adult attention-deficit/hyperactivity disorder (ADHD), 151 with familial ADHD, 189 suicide attempters, and 182 criminal offenders.

Main Outcome Measures  For the association studies, the major outcome criteria were phenotypes relevant to impulsivity, namely, the dimensional phenotype conscientiousness and the categorical phenotypes adult ADHD, aggression, and cluster B personality disorder.

Results  A novel functional promoter polymorphism in NOS1 was associated with traits related to impulsivity, including hyperactive and aggressive behaviors. Specifically, the short repeat variant was more frequent in adult ADHD, cluster B personality disorder, and autoaggressive and heteroaggressive behavior. This short variant came along with decreased transcriptional activity of the NOS1 exon 1f promoter and alterations in the neuronal transcriptome including RGS4 and GRIN1. On a systems level, it was associated with hypoactivation of the anterior cingulate cortex, which is involved in the processing of emotion and reward in behavioral control.

Conclusion  These findings implicate deficits in neuronal signaling via nitric oxide in moderation of prefrontal circuits underlying impulsivity-related behavior in humans.

Author Affiliations: Department of Psychiatry, Psychosomatics and Psychotherapy (Drs Reif, Jacob, Lang, Gutknecht, Fallgatter, Ehlis, and Lesch and Ms Baehne), Central Laboratory, Department of Clinical Biochemistry and Pathobiochemistry (Dr Herterich), and Department of Child and Adolescent Psychiatry and Psychotherapy (Drs Romanos and Renner), Julius-Maximilians-University Würzburg, and Interdisciplinary Center for Clinical Research, University of Würzburg (Drs Reif and Lesch), Würzburg, Germany; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany (Drs Rujescu, Giegling, and Hartmann); Department of Psychology, Johann Wolfgang Goethe University Frankfurt/Main, Frankfurt, Germany (Dr Strobel); and Department of Child and Adolescent Psychiatry (Dr Freitag) and Institute for Forensic Psychology and Psychiatry (Drs Rösler and Retz), Saarland University, Homburg, Germany.

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