Influence of functional variant of neuronal nitric oxide synthase on impulsive behaviors in humans.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


METHODS
Three psychiatric university clinics in Germany.


METHODS
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.


METHODS
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.


CONCLUSIONS
These findings implicate deficits in neuronal signaling via nitric oxide in moderation of prefrontal circuits underlying impulsivity-related behavior in humans.
Reif
Andreas
A
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Füchsleinstr 15, D-97080 Würzburg, Germany. reif_a@klinik.uni-wuerzburg.de
Jacob
Christian P
CP
Rujescu
Dan
D
Herterich
Sabine
S
Lang
Sebastian
S
Gutknecht
Lise
L
Baehne
Christina G
CG
Strobel
Alexander
A
Freitag
Christine M
CM
Giegling
Ina
I
Romanos
Marcel
M
Hartmann
Annette
A
Rösler
Michael
M
Renner
Tobias J
TJ
Fallgatter
Andreas J
AJ
Retz
Wolfgang
W
Ehlis
Ann-Christine
AC
Lesch
Klaus-Peter
KP
D000293:Adolescent; D000328:Adult; D000374:Aggression / Q000502:physiology*; D000483:Alleles; D001288:Attention / Q000502:physiology; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D004569:Electroencephalography; D018913:Event-Related Potentials, P300 / Q000235:genetics / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007175:Impulsive Behavior / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D009483:Neuropsychological Tests; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D010554:Personality Disorders / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D017397:Prefrontal Cortex / Q000503:physiopathology; D011329:Prisoners / Q000523:psychology*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011597:Psychomotor Performance / Q000502:physiology; D012016:Reference Values; D013406:Suicide, Attempted / Q000523:psychology*; D014754:Violence / Q000523:psychology; D055815:Young Adult
C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I