Quantitative magnetic resonance imaging traits as endophenotypes for genetic mapping in epilepsy

Abstract

Over the last decade, the field of imaging genomics has combined high-throughput genotype data with quantitative magnetic resonance imaging (QMRI) measures to identify genes associated with brain structure, cognition, and several brain-related disorders. Despite its successful application in different psychiatric and neurological disorders, the field has yet to be advanced in epilepsy. In this article we examine the relevance of imaging genomics for future genetic studies in epilepsy from three perspectives. First, we discuss prior genome-wide genetic mapping efforts in epilepsy, considering the possibility that some studies may have been constrained by inherent theoretical and methodological limitations of the genome-wide association study (GWAS) method. Second, we offer a brief overview of the imaging genomics paradigm, from its original inception, to its role in the discovery of important risk genes in a number of brain-related disorders, and its successful application in large-scale multinational research networks. Third, we provide a comprehensive review of past studies that have explored the eligibility of brain QMRI traits as endophenotypes for epilepsy. While the breadth of studies exploring QMRI-derived endophenotypes in epilepsy remains narrow, robust syndrome-specific neuroanatomical QMRI traits have the potential to serve as accessible and relevant intermediate phenotypes for future genetic mapping efforts in epilepsy.

Keywords: Endophenotypes; Epilepsy; Imaging genomics; Magnetic resonance imaging.

Fig. 1

The maximum effect sizes for the top individual common genetic variants (both for discovery and replication samples) from genome-wide association studies of brain structure (for example, hippocampal volume), schizophrenia (using traditional case:control design), and other anthropomorphic traits including height and educational attainment are shown (Franke et al., 2016). For quantitative traits, effect sizes were measured in percent variance explained. For disease categories, effect sizes were measured in percent variance explained on the liability scale. [Image is reproduced with permission from nature publishing group (Nature Neuroscience, 2016)].

Fig. 2

The distribution of hippocampal volume in the asymptomatic relatives of MTLE + HS patients and healthy controls is displayed (Tsai et al., 2013). (A): The symptomatic relatives (red) had smaller hippocampal volume relative to the healthy controls (blue). The same data is displayed in (B), with 90% confidence ellipse of the controls displayed in the blue oval, and 90% confidence ellipse of the relatives of probands with a positive family history (FH) displayed in the red oval. [Image is reproduced with permission from Wolters Kluwer Health, Inc. (Neurology, 2013)]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Whole-brain, voxel-wise comparisons of brain diffusion tensor imaging (DTI) measures, including fractional anisotropy (FA) and mean diffusivity (MD), in a group of patients with MRI-negative mesial temporal lobe epilepsy (MTLE), their asymptomatic siblings and healthy controls are shown (Whelan et al., 2015a). Patients with MTLE demonstrated patterns of reduced FA (illustrated in red) in voxel clusters encompassing the corpus callosum, ipsilateral anterior thalamic radiation, ipsilateral corticospinal tract (CST), bilateral superior longitudinal fasciculi (SLF), and bilateral inferior longitudinal fasciculi (ILF) compared to healthy controls. The asymptomatic siblings did not show significant FA compromise when compared to the same controls. Compared to controls, MTLE patients exhibited patterns of increased MD across the SLF bilaterally and the CST ipsilaterally (illustrated in blue). Similar patterns of increased MD along the ipsilateral SLF and ipsilateral CST (illustrated in yellow) were noted in the asymptomatic siblings. [Image is reproduced with permission from John Wiley and Sons (Epilepsia, 2015)]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)