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

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.

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

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

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.