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

Reif, Andreas; Kiive, Evelyn; Kurrikoff, Triin; Paaver, Marika; Herterich, Sabine; Konstabel, Kenn; Tulviste, Tiia; Lesch, Klaus‐Peter; Harro, Jaanus

doi:10.1007/s00213-010-1915-7

Cited by 41 publications

(47 citation statements)

References 20 publications

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“…Titles and abstracts were scrutinized to exclude non-genetic studies, reducing the number of included studies to Costain et al, 2010;Fang et al, 2008;Greenwood et al, 2011;Husted et al, 2010;Kremeyer et al, 2009;Miranda et al, 2006;Nicodemus et al, 2008;Wratten et al, 2009) and one on NOS1 (Fallin et al, 2005), presented family-based, but not case-control data and were therefore not integrated in the meta-analysis for methodological reasons. The remaining studies on NOS1AP (n=6; (Aberg et al, 2010;Delorme et al, 2010;Nicodemus et al, 2010;Puri et al, 2007;Puri et al, 2006;Zheng et al, 2005)) and NOS1 (n=14; (Cui et al, 2010;Donohoe et al, 2009;Kawohl et al, 2008;Nicodemus et al, 2010;O'Donoghue et al, 2012;Okumura et al, 2009;Reif et al, 2006;Reif et al, 2011;Riley et al, 2010;Rose et al, 2012;Shinkai et al, 2002;Silberberg et al, 2010;Tang et al, 2008;Wang et al, 2012)) reported on case-control association data and were scrutinized in greater detailed. For NOS1AP, two and for NOS1, 11 further studies had to be excluded from meta-analysis for the following reasons.…”

Section: Meta-analysismentioning

confidence: 99%

“…(Donohoe et al, 2009;Nicodemus et al, 2010;Riley et al, 2010) and (Shinkai et al, 2002) only presented data on SNPs which have not been genotyped for the present study; no SNP data could be obtained from the study of (Wang et al, 2012); and the study by (Silberberg et al, 2010) was excluded because of the rather small sample size (n=26) precluding meaningful interpretation of the data. Finally, (Reif et al, 2011) and (Reif et al, 2006), were excluded because the case samples of both studies overlapped with the sample described here (while the control sample was extended more than two-fold).…”

Section: Meta-analysismentioning

confidence: 99%

“…The functional promoter SNP rs41279104 was tested in studies using eventrelated potentials and functional near-infrared spectroscopy (Reif et al, 2006;Reif et al, 2011), providing evidence for a prefrontal deficit in risk allele carriers. In addition, Kawohl and associates (Kawohl et al, 2008) demonstrated that rs41279104 risk allele carriers had decreased loudness dependence of auditory evoked potentials, which is a functional marker of serotonergic transmission, arguing for a connection between the NO and serotonin systems as also shown on the protein and the neuronal network (Kiss and Vizi, 2001) level.…”

Section: Introductionmentioning

confidence: 99%

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The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis

Weber

Klamer

Freudenberg

et al. 2014

European Neuropsychopharmacology

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NO is a pleiotropic signaling molecule and has an important role for cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ interactions; this protein-protein interaction is disrupted upon binding of NOS1 adaptor protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratios of 1.29 in the metaanalysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia.

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Section: Meta-analysismentioning

confidence: 99%

Section: Meta-analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis

Weber

Klamer

Freudenberg

et al. 2014

European Neuropsychopharmacology

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“…Targeted disruption of Nos1 in mice increased impulsivity and aggressiveness, reduced anxiety, and impaired learning (19,20). Human behavioral and imaging studies have shown NOS1 exon 1f-VNTR to be associated with hyperactive, impulsive, and aggressive behavior as well as hypofunctioning of the anterior cingulate cortex (15,21,22).Although the NOS1 gene has been linked to ADHD, impulsivity, and modification of neurotransmitter levels in the striatum, effects of NOS1 genetic variation on striatal activity have not been investigated. The objective of the present study was to better understand the effect of this gene on neurobiological dysfunctioning in adult ADHD by exploring the influence of the exon 1f-VNTR on impulsivity and reward-related striatal activity in a large sample of adult ADHD patients (N=87) and healthy comparison subjects (N=49).…”

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confidence: 99%

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

Hoogman¹,

Aarts²,

Zwiers³

et al. 2011

AJP

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(5), as evidenced by steeper temporal discounting rates, altered decision making, and an aversion to delay of gratification in reward-related tests (6-9). Temporal discounting is the patient's preference to receive smaller rewards sooner rather than larger rewards later and is postulated to be an intermediate phenotype for impulsivity. Neuroimaging studies have shown engagement of alternative brain regions in decision making in ADHD patients (10). A prominent feature is hypoactivation of the ventral striatum, a brain area with an important role in reward processing (11,12), during reward anticipation (13,14). Ventral striatal activity is also associated with impulsivity, a hallmark of ADHD (12,13). Recently, the NOS1 gene was identified as a candidate gene for ADHD and other impulsivity disorders (15). A variant in this gene was also among the top findings of a genome-wide association study in ADHD (3). NOS1 encodes nitric oxide synthase 1. Nitric oxide, the product of this enzyme's activity, acts as the second messenger downstream of the N-methyl-d-aspartate receptor and interacts with both the dopaminergic and serotonergic systems in the human brain. Nitric oxide inhibits monoamine transporters, thereby modulating the dopamine and noradrenalin concentration in the extracellular space (16). In addi-(A m J P sy c h ia try 2 0 1 1 ; 1 6 8 :1 0 9 9 -1 1 0 6 ) N itric O x id e S y n th a se G e n o ty p e M o d u la tio n o f Im p u lsiv ity a n d Ve n tra l S tria ta l A c tiv ity in A d u lt A D H D P a tie n ts a n d H e a lth y C o m p a riso n S u b je c ts O b je c tiv e : Attention deficit hyperactivity disorder (AD HD ) is a highly heritable disorder. The NO S1 gene encoding nitric oxide synthase is a candidate gene for AD HD and has been previously linked w ith im pulsivity. In the present study, the authors investigated the effect of a functional variable num ber of tandem repeats (VNTR ) polym orphism in NO S1 (NO S1 exon 1f-VNTR ) on the processing of rew ards, one of the cognitive deficits in AD HD. M e th o d :A sam ple of 136 participants, consisting of 87 adult AD HD patients and 49 healthy com parison subjects, completed a rew ard-related im pulsivity task. A total of 104 participants also underw ent functional m agnetic resonance im aging during a rew ard anticipation task. The effect of the NO S1 exon 1f-VNTR genotype on rew ard-related im pulsivity and rew ard-related ventral striatal activity w as exam ined.R e s u lts : AD HD patients had higher impulsivity scores and low er ventral striatal activity than healthy com parison subjects. The association betw een the short allele and increased im pulsivity w as confirm ed. How ever, independent of disease status, hom ozygous carriers of the short allele of NO S1, the AD HD risk genotype, dem onstrated higher ventral striatal activity than carriers of the other NO S1 VNTR genotypes.C o n c lu s io n s : The authors suggest that the NO S1 genotype influences im pulsivity and its relation w ith AD HD is m ediated through effects on this behavioral tr...

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“…Nugent et al (2011) review this work with respect to the risk for developing depressive and anxiety disorders in adolescence and adulthood. Reif et al (2010) demonstrate how adaptive and maladaptive impulsivity reflect interactions of neuronal nitric oxide synthase (NOS1) genotype with adverse family environment and stressful life events in adolescents. In their epidemiological study, Elzinga et al (2010) report that brain-derived neurotrophic factor (BDNF) genotype interacts with ELS and recent life stress to lower serum BDNF levels in adults with a history of depression.…”

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confidence: 99%

Early life stress and psychopharmacology

Price

Steckler

2011

Psychopharmacology

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The concept of early life stress (ELS) has long been a central focus in clinical psychiatry and psychology, owing in no small part to the primacy of this concept in psychoanalytic theory. Perhaps in response to that legacy, both clinical and preclinical biologically oriented researchers have become increasingly invested in understanding the adult sequelae of adverse environmental factors occurring early in development.Several factors stand out in considering the drivers of this changing zeitgeist: (1) new efforts to integrate preclinical and clinical findings on the pathogenesis of major psychiatric disorders, especially by focusing on model neurobiological systems (e.g., Heim et al. 1997); (2) empirical demonstration of the relevance of the classic diathesis-stress theory using gene×environment (G×E) experimental designs (e.g., Caspi et al. 2003) and, more recently, epigenetic approaches (e.g., McGowan and Szyf 2010); (3) increased recognition of the adverse psychiatric and biomedical sequelae of ELS (e.g., Gluckman and Hanson 2004;Scott et al. 2010); (4) convincing demonstration of ELS as a major global public health challenge (e.g., Krug et al. 2002). The diversity of work covered in this Special Issue reflects the remarkable progress that has been made in this area in a relatively brief span of time. Long-term cognitive sequelae of ELS are now well documented, and two reviews in this issue address this burgeoning literature. Hedges and Woon (2010) organize the findings with an emphasis on specific functional effects, while Pechtel and Pizzagali (2010) utilize a neurodevelopmental framework to integrate observations on cognitive and affective processes.The seminal preclinical studies of ELS and the HPA axis (Claessens et al.

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

Cited by 41 publications

References 20 publications

The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis

The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis

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

Early life stress and psychopharmacology

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