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

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)958-966
Number of pages9
JournalJournal of Child Psychology and Psychiatry
Volume58
Issue number8
DOIs
Publication statusPublished - 2017

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Attention Deficit Disorder with Hyperactivity
Genotype
Exons
Alleles
White Matter
Diffusion Tensor Imaging
Impulsive Behavior
Anisotropy
Brain
Nitric Oxide Synthase

Keywords

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

Cite this

van Ewijk, Hanneke ; Bralten, Janita ; van Duin, Esther D.A. ; Hakobjan, Marina ; Buitelaar, Jan K. ; Heslenfeld, Dirk J. ; Hoekstra, Pieter J. ; Hartman, Catharina ; Hoogman, Martine ; Oosterlaan, Jaap ; Franke, Barbara. / Female-specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls. In: Journal of Child Psychology and Psychiatry. 2017 ; Vol. 58, No. 8. pp. 958-966.
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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 = "attention-deficit/hyperactivity disorder, diffusion tensor imaging, imaging genetics, NOS1",
author = "{van Ewijk}, Hanneke and Janita Bralten and {van Duin}, {Esther D.A.} and Marina Hakobjan and Buitelaar, {Jan K.} and Heslenfeld, {Dirk J.} and Hoekstra, {Pieter J.} and Catharina Hartman and Martine Hoogman and Jaap Oosterlaan and Barbara Franke",
year = "2017",
doi = "10.1111/jcpp.12742",
language = "English",
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van Ewijk, H, Bralten, J, van Duin, EDA, Hakobjan, M, Buitelaar, JK, Heslenfeld, DJ, Hoekstra, PJ, Hartman, C, Hoogman, M, Oosterlaan, J & Franke, B 2017, 'Female-specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls' Journal of Child Psychology and Psychiatry, vol. 58, no. 8, pp. 958-966. https://doi.org/10.1111/jcpp.12742

Female-specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls. / van Ewijk, Hanneke; Bralten, Janita; van Duin, Esther D.A.; Hakobjan, Marina; Buitelaar, Jan K.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Hartman, Catharina; Hoogman, Martine; Oosterlaan, Jaap; Franke, Barbara.

In: Journal of Child Psychology and Psychiatry, Vol. 58, No. 8, 2017, p. 958-966.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Female-specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls

AU - van Ewijk, Hanneke

AU - Bralten, Janita

AU - van Duin, Esther D.A.

AU - Hakobjan, Marina

AU - Buitelaar, Jan K.

AU - Heslenfeld, Dirk J.

AU - Hoekstra, Pieter J.

AU - Hartman, Catharina

AU - Hoogman, Martine

AU - Oosterlaan, Jaap

AU - Franke, Barbara

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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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KW - diffusion tensor imaging

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