Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Aug;58(8):958-966.
doi: 10.1111/jcpp.12742. Epub 2017 Jun 7.

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

Hanneke van Ewijk  1 , Janita Bralten  2   3 , Esther D A van Duin  4 , Marina Hakobjan  2 , Jan K Buitelaar  3   5   6 , Dirk J Heslenfeld  1 , Pieter J Hoekstra  7 , Catharina Hartman  7 , Martine Hoogman  2   3 , Jaap Oosterlaan  1 , Barbara Franke  2   3   8
Affiliations

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

Hanneke van Ewijk et al. J Child Psychol Psychiatry. 2017 Aug.

Abstract

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.

Keywords: NOS1; attention-deficit/hyperactivity disorder; diffusion tensor imaging; imaging genetics.

PubMed Disclaimer

Conflict of interest statement

The remaining authors declare no competing or potential conflicts of interest.

Figures

Figure 1
Figure 1
Schematic overview of the sample, stratified by the main predictors in the analyses: Diagnostic group (ADHD versus controls), genotype (risk [S/S] versus other [S/L and L/L]), and gender (male versue female).
Figure 2
Figure 2
Main results from the voxelwise tract-based spatial statistics (TBSS) analysis. For visualisation of the interaction between NOS1 genotype and gender, mean MD value derived from all significant clusters are plotted, stratified by gender. Note. Results are overlaid on a standard MNI152 template with the mean skeleton in green (FA>0.3), and were “thickened” towards the full width of the tract for visualization purposes.
Figure 3
Figure 3
Results from the follow-up analysis, showing an association between NOS1 genotype and mean diffusivity (MD) specifically in females (n=113). Note. Results are overlaid on a standard MNI152 template with the mean skeleton in green (FA>0.3), and were “thickened” towards the full width of the tract for visualization purposes.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. ALEXANDER AL, LEE JE, LAZAR M, FIELD AS. Diffusion tensor imaging of the brain. Neurotherapeutics. 2007;4:316–329. - PMC - PubMed
    1. AMERICAN PSYCHIATRIC ASSOCIATION. Diagnostic and statistical manual of mental disorders: DSM-IV-TR. American Psychiatric Publishing, Inc; 2000.
    1. AMERICAN PSYCHIATRIC ASSOCIATION. The Diagnostic and Statistical Manual of Mental Disorders: DSM 5. bookpointUS; 2013.
    1. CASEY BJ, EPSTEIN JN, BUHLE J, LISTON C, DAVIDSON MC, TONEV ST, SPICER J, NIOGI S, MILLNER AJ, REISS A, GARRETT A, HINSHAW SP, GREENHILL LL, SHAFRITZ KM, VITOLO A, KOTLER LA, JARRETT MA, GLOVER G. Frontostriatal connectivity and its role in cognitive control in parent-child dyads with ADHD. American Journal of Psychiatry. 2007;164:1729–1736. - PubMed
    1. CHEN J, ZACHAREK A, LI Y, LI A, WANG L, KATAKOWSKI M, ROBERTS C, LU M, CHOPP M. N-cadherin mediates nitric oxide-induced neurogenesis in young and retired breeder neurospheres. Neuroscience. 2006;140:377–388. - PMC - PubMed

Substances