Nitric Oxide Synthase Genotype Modulation of Impulsivity and Ventral Striatal Activity in Adult ADHD Patients and Healthy Comparison Subjects

• Published in: American Journal of Psychiatry Vol. 168; no. 10; pp. 1099 - 1106
• Main Authors: Hoogman, Martine, Aarts, Esther, Zwiers, Marcel, Slaats-Willemse, Dorine, Naber, Marlies, Onnink, Marten, Cools, Roshan, Kan, Cornelis, Buitelaar, Jan, Franke, Barbara
• Format: Journal Article
• Language: English
• Published: Arlington, VA American Psychiatric Publishing 01.10.2011; American Psychiatric Association
• Subjects: Adult; Adult and adolescent clinical studies; Adults; Alleles; Attention Deficit Disorder with Hyperactivity - genetics; Attention Deficit Disorder with Hyperactivity - physiopathology; Attention Deficit Disorder with Hyperactivity - psychology; Attention deficit hyperactivity disorder; Basal Ganglia - physiopathology; Biological and medical sciences; Brain Mapping; Cognition & reasoning; Female; Genotype; Genotype & phenotype; Humans; Hyperactivity; Image Processing, Computer-Assisted; Impulsive Behavior - genetics; Impulsive Behavior - physiopathology; Impulsive Behavior - psychology; Magnetic Resonance Imaging; Male; Medical sciences; Middle Aged; Miscellaneous; Neuropsychological Tests; Nitric oxide; Nitric Oxide Synthase Type I - genetics; Phenotype; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Tandem Repeat Sequences; Human; Impulsivity; Enzyme; Central nervous system; Genotype; Basal ganglion; Corpus striatum; Experimental study; Metabolism; Tandemly repeated sequence; Genetic determinism; Nitric-oxide synthase; Encephalon; Functional magnetic resonance imaging; Genetics; Attention disorder with hyperactivity; Oxidoreductases; Polymorphism
• ISSN: 0002-953X; 1535-7228; 1535-7228
• DOI: 10.1176/appi.ajp.2011.10101446

Since ADHD and, in particular, impulsivity are related to decreased ventral striatal activity, it was hypothesized that the NOS1 genotype itself might also be related to decreased ventral striatal activity. However, the authors found instead that NOS1 variants associated with ADHD are actually associated with increased ventral striatal activity. Thus, the effect of NOS1 must involve a change in activity elsewhere in the brain, and the decreased ventral striatal activity must happen through other mechanisms. Objective:Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder. The NOS1 gene encoding nitric oxide synthase is a candidate gene for ADHD and has been previously linked with impulsivity. In the present study, the authors investigated the effect of a functional variable number of tandem repeats (VNTR) polymorphism in NOS1 (NOS1 exon 1f-VNTR) on the processing of rewards, one of the cognitive deficits in ADHD. Method:A sample of 136 participants, consisting of 87 adult ADHD patients and 49 healthy comparison subjects, completed a reward-related impulsivity task. A total of 104 participants also underwent functional magnetic resonance imaging during a reward anticipation task. The effect of the NOS1 exon 1f-VNTR genotype on reward-related impulsivity and reward-related ventral striatal activity was examined. Results:ADHD patients had higher impulsivity scores and lower ventral striatal activity than healthy comparison subjects. The association between the short allele and increased impulsivity was confirmed. However, independent of disease status, homozygous carriers of the short allele of NOS1, the ADHD risk genotype, demonstrated higher ventral striatal activity than carriers of the other NOS1 VNTR genotypes. Conclusions:The authors suggest that the NOS1 genotype influences impulsivity and its relation with ADHD is mediated through effects on this behavioral trait. Increased ventral striatal activity related to NOS1 may be compensatory for effects in other brain regions.