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

Hanneke van Ewijk*, Janita Bralten, Esther D.A. van Duin, Marina Hakobjan, Jan K. Buitelaar, Dirk J. Heslenfeld, Pieter J. Hoekstra, Catharina Hartman, Martine Hoogman, Jaap Oosterlaan, Barbara Franke

*Corresponding author for this work

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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.

Original languageEnglish
Pages (from-to)958-966
Number of pages9
JournalJournal of Child Psychology and Psychiatry
Issue number8
Early online date7 Jun 2017
Publication statusPublished - Aug 2017


This work was supported by NIH Grant R01MH62873 and R01MH081803, NWO Large Investment Grant 1750102007010, ZonMW Grant 60-60600-97-193 and NWO Brain and Cognition grant 433-09-242 to J.K.B., and grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and VU University Amsterdam. The research leading to these results also received funding from the European Community's Seventh Framework Programme (FP7/2007? 2013) under grant agreement no 278948 (TACTICS), no. 305697 (OPTIMISTIC), no. 602805 (Aggressotype), no. 603036 (MATRICS), and no. 602450 (IMAGEMEND) and from the Horizon2020 Marie-Curie ETN grant no. 643051 (MiND). B.F. is supported by a Vici grant from NWO (grant number 016-130-669) and she and J.K.B. received funding from the National Institutes of Health (NIH) Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centers of Excellence (BD2K). The authors thank all families that participated in this study and all researchers who collected the data. Furthermore, we acknowledge the department of Pediatrics of the VU university Medical Center for having the opportunity to use the mock scanner for preparation of our participants. J.O. has received unrestricted investigator initiated research grants from Shire pharmaceuticals. B.F. received an?educational speaking fee from Merz. J.K.B. has been in the past 3?years a consultant to / member of advisory board of / and/or speaker for Janssen Cilag BV, Eli Lilly, Lundbeck, Shire, Roche, Novartis, Medice and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, or royalties. P.J.H. has in the past 3?years been an advisory board member of Shire. The remaining authors declare no competing or potential conflicts of interest.

FundersFunder number
Horizon2020 Marie-Curie643051
VU University Medical Center
National Institutes of HealthU54 EB020403
National Institute of Mental HealthR01MH062873
Seventh Framework Programme602805, 602450, 305697, 603036, 278948
ZonMw60-60600-97-193, 433-09-242
Vrije Universiteit Amsterdam
Nederlandse Organisatie voor Wetenschappelijk Onderzoek1750102007010
Seventh Framework Programme
Radboud Universitair Medisch Centrum


    • attention-deficit/hyperactivity disorder
    • diffusion tensor imaging
    • imaging genetics
    • NOS1


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