Article

A functional NOS1 promoter polymorphism interacts with adverse environment on functional and dysfunctional impulsivity.

Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Füchsleinstr. 15, 97080, Würzburg, Germany.
Psychopharmacology (Impact Factor: 3.99). 03/2011; 214(1):239-48. DOI: 10.1007/s00213-010-1915-7
Source: PubMed

ABSTRACT Neuronal nitric oxide synthase (NOS1) knockout results in increased impulsive aggression in mice under adverse housing conditions. In line with this, we have previously shown that a functional promoter polymorphism of NOS1, termed NOS1 ex1f-VNTR, is associated with impulsivity-related traits and related disorders.
This study aims to examine whether adverse environment interacts with the risk allele on impulsivity-related measures.
We here studied a population-based cohort of Estonian pupils, recruited at the age of 9 years and followed up for another 9 years. For 435 subjects, measures on impulsivity (Adaptive and Maladaptive Impulsivity Scale, BIS-11, Stop Signal data, and Visual Comparison Test, VCT), environmental conditions (stressful life events and family environment), and NOS1 ex1f-VNTR genotype were available.
We found a genotype main effect in that presence of a short NOS1 ex1f-VNTR allele was associated with higher levels of adaptive impulsivity, especially in males, but also worse performance in the VCT and the Stop Signal test. Both stressful life events as well as adverse family environment interacted with the risk genotype to increase maladaptive impulsivity.
This study provides further evidence that short alleles of NOS1 ex1f-VNTR go along with impulsive behavior. In the absence of adverse environmental conditions, this may lead to a beneficial effect as functional forms of impulsivity are affected. This however is reversed under negative conditions, as dysfunctional impulsivity is increased under these circumstances. This data provides evidence that NOS1 ex1f-VNTR is subject to balancing selection potentially explaining persistence of the risk allele in the population.

0 Followers
 · 
227 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: NO is a gaseous transmitter produced by nitric oxide synthases (NOSs). The neuronal isoform (NOS-I, encoded by NOS1) is the main source of NO in the CNS. Animal studies suggest that nitrinergic dysregulation may lead to behavioral abnormalities. Unfortunately, the large number of animal studies is not adequately reflected by publications concerning humans. These include postmortem studies, determination of biomarkers, and genetic association studies. Here, we review the evidence for the role of NO in psychiatric disorders by focusing on the human NOS1 gene as well as biomarker studies. Due to the complex regulation of NOS1 and the varying function of NOS-I in different brain regions, no simple, unidirectional association is expected. Rather, the "where, when and how much" of NO formation is decisive. Present data, although still preliminary and partially conflicting, suggest that genetically driven reduced NO signaling in the prefrontal cortex is associated with schizophrenia and cognition. Both NOS1 and its interaction partner NOS1AP have a role therein. Also, reduced NOS1 expression in the striatum determined by a length polymorphism in a NOS1 promoter (NOS1 ex1f-VNTR) goes along with a variety of impulsive behaviors. An association of NOS1 with mood disorders, suggested by animal models, is less clear on the genetic level; however, NO metabolites in blood may serve as biomarkers for major depression and bipolar disorder. As the nitrinergic system comprises a relevant target for pharmacological interventions, further studies are warranted to elucidate the pathophysiology of mental disorders, but also to evaluate NO function as a biomarker. This article is protected by copyright. All rights reserved.
    Genes Brain and Behavior 01/2015; DOI:10.1111/gbb.12193 · 3.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The functional polymorphism Asn107Ile (rs324981, A > T) of the neuropeptide S receptor (NPSR1) gene is involved in the modulation of traits that affect alcohol use. Hence, we have examined whether the NPSR1 A/T polymorphism is associated with alcohol use disorders (AUD) and alcohol use in a population-representative sample. Lifetime AUD were assessed by the MINI psychiatric interview (n = 501) in the older cohort of the longitudinal Estonian Children Personality Behaviour and Health Study at age 25. Alcohol use, environmental adversities and personality were reported by both the younger (original n = 583) and the older cohort (original n = 593) in three study waves. NPSR1 associations with AUD and alcohol use differed by sex. In females, both AUD [odds ratio (OR) = 7.20 (0.94–55.0), P = 0.029] and harmful alcohol use were more prevalent in A-allele carriers. In contrast, in males, AUD was more frequent in T-allele carriers [OR = 2.75 (1.19–6.36), P = 0.017], especially if exposed to adverse environments at age 15 [OR = 10 (1.18–84.51), P = 0.019]. Alcohol use was higher in male T-allele carriers at ages 15 and 18 as well. Similarly to females, however, the risk allele for higher alcohol use for males at age 25 was the A-allele. Many of the effects on alcohol use were explained by genotype effects on measures of personality. In the general population, the NPSR1 Asn107Ile polymorphism is associated with AUD and alcohol consumption, dependent on sex, environment and age. The results are in line with the impulsivity and personality regulating role of the NPSR1.
    Addiction Biology 05/2014; 20(3). DOI:10.1111/adb.12149 · 5.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is increasing evidence that genetic factors play a role in differential susceptibility to depression in response to severe or chronic adversity. Studies in animals suggest that nitric oxide (NO) signalling plays a key role in depression-like behavioural responses to stress. This study investigated whether genetic variation in the brain-expressed nitric oxide synthase gene NOS1 modifies the relationship between psychosocial stress and current depression score. We recruited a population sample of 1222 individuals who provided DNA and questionnaire data on symptoms and stress. Scores on the List of Life-Threatening Experiences (LTE) questionnaire for the last year and self-rated current financial hardship were used as measures of recent/ongoing psychosocial stress. Twenty SNPs were genotyped. Significant associations between 8 NOS1 SNPs, comprising two regional haplotypes, and current depression score were identified that survived correction for multiple testing when current financial hardship was used as the interaction term. A smaller 3 SNP haplotype (rs10507279, rs1004356, rs3782218) located in a regulatory region of NOS1 showed one of the strongest effects, with the A-C-T haplotype associating with higher depression scores at low adversity levels but lower depression scores at higher adversity levels (p=2.3E-05). These results suggest that NOS1 SNPs interact with exposure to economic and psychosocial stressors to alter individual's susceptibility to depression.Neuropsychopharmacology accepted article preview online, 11 June 2014; doi:10.1038/npp.2014.137.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2014; DOI:10.1038/npp.2014.137 · 8.68 Impact Factor

Full-text (6 Sources)

Download
234 Downloads
Available from
May 26, 2014