Heritability of complex white matter diffusion traits assessed in a population isolate

Abstract

Introduction: Diffusion weighted imaging (DWI) methods can noninvasively ascertain cerebral microstructure by examining pattern and directions of water diffusion in the brain. We calculated heritability for DWI parameters in cerebral white (WM) and gray matter (GM) to study the genetic contribution to the diffusion signals across tissue boundaries.

Methods: Using Old Order Amish (OOA) population isolate with large family pedigrees and high environmental homogeneity, we compared the heritability of measures derived from three representative DWI methods targeting the corpus callosum WM and cingulate gyrus GM: diffusion tensor imaging (DTI), the permeability-diffusivity (PD) model, and the neurite orientation dispersion and density imaging (NODDI) model. These successively more complex models represent the diffusion signal modeling using one, two, and three diffusion compartments, respectively.

Results: We replicated the high heritability of the DTI-based fractional anisotropy (h(2) = 0.67) and radial diffusivity (h(2) = 0.72) in WM. High heritability in both WM and GM tissues were observed for the permeability-diffusivity index from the PD model (h(2) = 0.64 and 0.84), and the neurite density from the NODDI model (h(2) = 0.70 and 0.55). The orientation dispersion index from the NODDI model was only significantly heritable in GM (h(2) = 0.68).

Conclusion: DWI measures from multicompartmental models were significantly heritable in WM and GM. DWI can offer valuable phenotypes for genetic research; and genes thus identified may reveal mechanisms contributing to mental and neurological disorders in which diffusion imaging anomalies are consistently found. Hum Brain Mapp 37:525-535, 2016. © 2015 Wiley Periodicals, Inc.

Keywords: DTI; DWI; genetics; heritability; imaging.

Figure 1

Upper panel: (A) Corpus callosum (CC) white matter (WM) region‐of‐interest was identified by thresholding the FA image at FA = 0.20. The skeleton of the midsagittal colossal WM measured using the ENIGMA‐DTI pipeline is shown as colored line with the magnitude of FA values represented by colors and overlaid on the fractional anisotropy map at midline. (B) The region of interest for cingulate gray matter (GM) was identified using radial diffusivity maps that show excellent contrast between GM, WM, and CSF. Lower panel: schematic comparison of the DTI model (C), permeability‐diffusivity (PD) model (D), and Neurite orientation dispersion and density imaging (NODDI) model (E). The DTI model assumes that the signal is produced by a single pool of anisotropically diffusing water and characterizes this anisotropy using fractional anisotropy (FA). The PD‐model, developed by Sukstanskii et al. (2004), assumes that the signal is produced by two quasi‐pools of isotropically diffusing water. Unrestricted pool (M _u) is produced by water molecules that are sufficiently away from the cellular membranes to be unaffected by them. The water near the membrane forms the restricted compartment (1 − M _u) whose diffusivity depends on both the passive diffusivity of water through the cellular/myelin membrane and the active (thick arrow) permeability via the ionic channels and water pores that use water as a substrate for compartment exchange. The NODDI model, developed by Zhang et al. (2012) assumes contribution from three compartments: the unrestricted diffusion compartment (M _iso), intracellular (M _ic), and extra cellular (1 − M _ic). Neurites (neurons or axons) are expected to have a given angular distribution about the principle axis that is characterized by the orientation dispersion index (ODI). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 2

Heritability values for DWI parameters measured in white matter (WM) and gray matter (GM), the bars represent standard error of the mean. *Significant heritability estimate (P < 0.05).