On the role of <i>NOS1</i> ex1f‐VNTR in ADHD—allelic, subgroup, and meta‐analysis

Weber, Heike; Kittel‐Schneider, Sarah; Heupel, Julia; Weissflog, L.; Kent, Lindsey; Freudenberg, Florian; Alttoa, Aet; Post, Antonia; Herterich, Sabine; Haavik, Jan; Halmøy, Anne; Fasmer, Ole Bernt; Landaas, Elisabeth Toverud; Johansson, Stefan; Cormand, Bru; Ribasés, Marta; Sánchez-Mora, Cristina; Ramos-Quiroga, Josep Antoni; Franke, Barbara; Lesch, Klaus‐Peter; Reif, Andreas

doi:10.1002/ajmg.b.32326

Cited by 21 publications

(20 citation statements)

References 47 publications

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“…We replicated previously observed associations of NOS1 with specifically hyperactive/impulsive and total ADHD symptoms, but not the inattentive symptoms (Reif et al., ; Weber et al., ) in an independent sample. These findings extend previous findings by showing that this association is also observed in children and adolescents.…”

Section: Discussionsupporting

confidence: 90%

“…The association of NOS1 genotype and WM properties was only present in females. A female specificity of the NOS1 effects was indeed expected based on the earlier studies linking the exon 1f variant to ADHD status and ADHD-like symptoms (Reif et al, 2009;Weber et al, 2015). One possible explanation could be given by the fact that the promoter region of exon 1f harbours an oestrogen binding site (Reif et al, 2009), and a link between oestrogen and upregulation of nitric oxide synthases has indeed been found (Nuedling et al, 2001).…”

Section: Discussionmentioning

confidence: 67%

“…A significant excess of S alleles has been found in adults with ADHD (Reif et al., ). Homozygosity for the short allele appears to be specifically related to hyperactive‐impulsive behaviour, and the hyperactive‐impulsive and combined types of ADHD (Reif et al., ; Tanda et al., ; Weber et al., ). The association between the NOS1 VNTR and ADHD symptoms appears to be gender‐specific; both the original study as well as a recent meta‐analysis showed that the association of NOS1 with ADHD and impulsive behaviour was only present in females (Reif et al., ; Weber et al., ).…”

Section: Introductionmentioning

confidence: 99%

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Female‐specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls

Ewijk

Bralten

Duin

et al. 2017

Child Psychology Psychiatry

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Background The nitric oxide synthase gene (NOS1) exon 1f (ex1f) VNTR is a known genetic risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD), particularly in females. NOS1 plays an important role in neurite outgrowth and may thus influence brain development, specifically white matter (WM) microstructure, which is known to be altered in ADHD. The current study aimed to investigate whether NOS1 is associated with WM microstructure in (female) individuals with and without ADHD. Methods Diffusion Tensor Imaging (DTI) scans were collected from 187 participants with ADHD (33% female) and 103 controls (50% female), aged 8–26 years, and NOS1-ex1f VNTR genotype was determined. Whole-brain analyses were conducted for fractional anisotropy (FA) and mean diffusivity (MD) to examine associations between NOS1 and WM microstructure, including possible interactions with gender and diagnosis. Results Consistent with previous literature, NOS1-ex1f was associated with total ADHD and hyperactivity-impulsivity symptoms, but not inattention; this effect was independent of gender. NOS1-ex1f was also associated with MD values in several major WM tracts in females, but not males. In females, homozygosity for the short allele was linked to higher MD values than carriership of the long allele. MD values in these regions did not correlate with ADHD symptoms. Results were similar for participants with and without ADHD. Conclusions NOS1-ex1f VNTR is associated with WM microstructure in females in a large sample of participants with ADHD and healthy controls. Whether this association is part of a neurodevelopmental pathway from NOS1 to ADHD symptoms should be further investigated in future studies.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

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Female‐specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls

Ewijk

Bralten

Duin

et al. 2017

Child Psychology Psychiatry

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“…Despite this considerable heritability, the identification of risk genes has been challenging [3,7], and one reason for this could be the genetic complexity of the disease. Identified candidate genes so far mainly belong to monoaminergic neurotransmitter pathways, especially dopaminergic and serotonergic signaling [8][9][10][11][12]. Different (hypothesis-free) approaches, including genomewide linkage analyses and genome-wide association studies (GWASs), have been performed in order to detect additional genetic factors for ADHD.…”

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confidence: 99%

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

et al. 2018

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Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (N total = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.

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“…In addition to this, we also included genes with reported and replicated evidence for association with ADHD from more recent studies. These included two meta-analytic studies (Pan et al, 2015;Wu et al, 2012), a research article (Ribases et al, 2011), and the more recently observed replicated candidate genes NOS1 and SLC9A9 (Stergiakouli et al, 2012;Weber et al, 2015) (total number of candidate genes = 10; Table 1). A recent overview of these ADHD candidate genes has been published by Hawi et al (2015).…”

Section: Candidate Gene Selection For Adhd Asd and Id Studiesmentioning

confidence: 99%

Imaging genetics in neurodevelopmental psychopathology

Klein

Donkelaar

Verhoef

et al. 2017

American J of Med Genetics Pt B

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Neurodevelopmental disorders are defined by highly heritable problems during development and brain growth. Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), and intellectual disability (ID) are frequent neurodevelopmental disorders, with common comorbidity among them. Imaging genetics studies on the role of disease-linked genetic variants on brain structure and function have been performed to unravel the etiology of these disorders. Here, we reviewed imaging genetics literature on these disorders attempting to understand the mechanisms of individual disorders and their clinical overlap. For ADHD and ASD, we selected replicated candidate genes implicated through common genetic variants. For ID, which is mainly caused by rare variants, we included genes for relatively frequent forms of ID occurring comorbid with ADHD or ASD. We reviewed case-control studies and studies of risk variants in healthy individuals. Imaging genetics studies for ADHD were retrieved for SLC6A3/DAT1, DRD2, DRD4, NOS1, and SLC6A4/5HTT. For ASD, studies on CNTNAP2, MET, OXTR, and SLC6A4/5HTT were found. For ID, we reviewed the genes FMR1, TSC1 and TSC2, NF1, and MECP2. Alterations in brain volume, activity, and connectivity were observed. Several findings were consistent across studies, implicating, for example, SLC6A4/5HTT in brain activation and functional connectivity related to emotion regulation. However, many studies had small sample sizes, and hypothesis-based, brain region-specific studies were common. Results from available studies confirm that imaging genetics can provide insight into the link between genes, disease-related behavior, and the brain. However, the field is still in its early stages, and conclusions about shared mechanisms cannot yet be drawn.

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On the role of NOS1 ex1f‐VNTR in ADHD—allelic, subgroup, and meta‐analysis

Cited by 21 publications

References 47 publications

Female‐specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls

Female‐specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

Imaging genetics in neurodevelopmental psychopathology

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