The impact of a Dysbindin schizophrenia susceptibility variant on fiber tract integrity in healthy individuals: A TBSS-based diffusion tensor imaging study
Highlights
► Genomic imaging study enrolling 101 healthy RWTH students. ► Impact of a schizophrenia risk gene variant on structural brain connectivity. ► Minor T allele carriers showed reduced FA values in the right perihippocampal region. ► Six clusters of increased FA values were found in T-allele. ► Reduced anatomic connectivity may result in increased risk for schizophrenia.
Introduction
While the exact etiopathogenesis of schizophrenias is still unknown, the view of a largely genetically determined disorder associated with anomalies in brain structure and function is widely accepted (Harrison and Weinberger, 2005). Findings of structural MRI studies have generally demonstrated enlarged lateral ventricles and subtle pathological changes in frontal and temporal regions, especially volume reductions of the hippocampus, the superior temporal gyrus (STG) and the dorsolateral prefrontal cortex (DLPFC) in patients (Shenton et al., 2001). Since hypotheses on the underlying pathophysiology of schizophrenia have repeatedly taken dysfunctional connectivity into focus (Harrison and Weinberger, 2005, Stephan et al., 2006), a growing number of studies has aimed at identifying abnormalities of white matter and structural connectivity in schizophrenia. Several MRI studies have demonstrated white matter anomalies in schizophrenia patients, mainly in frontal and temporal white matter (Ashtari et al., 2007, Buchsbaum et al., 2006, Cheung et al., 2008, Ellison-Wright and Bullmore, 2009, Stephan et al., 2009, Szeszko et al., 2008).
As well as pathological associations with brain structure there have been a number of successful studies combining genetic data with neuroimaging data. Genetic imaging studies were able to identify correlations between schizophrenia risk gene variants and brain structure anomalies (Nickl-Jockschat et al., 2009). Most of these studies, however, have focused on structural changes within the gray matter. Conversely only three studies have yet been published dealing with the correlation of white matter anomalies and schizophrenia risk gene variants (Konrad et al., 2009, McIntosh et al., 2008, Winterer et al., 2008).
The dystrobrevin-binding protein 1 (DTNBP1) is of special interest for such a neuroimaging study. In addition, Dysbindin has been ranked as one of the most important candidates for schizophrenia identified to date (Sun et al., 2008).
The single nucleotide polymorphism (SNP) rs1018381 located in the Dysbindin gene has been found to be associated with schizophrenia and general cognitive abilities.
In a recent metaanalysis, using an approach based on the EM algorithm that detects allelic heterogeneity and assigns studies to subpopulations of analyzed markers, Maher et al. (2010) identified four SNPs to be most significantly associated with schizophrenia (Woolf test p < 0.0001) in genetic association studies in Caucasians. Among these four SNPs, rs1018381 is the strongest tagging SNP (HapMap2 CEU). The study of Burdick et al. (2006) found the minor T allele to be associated with general cognitive ability. The allele associated with schizophrenia is not consistent. In 10 studies the T allele was found to be associated with the disorder and in seven studies it was the C allele (Maher et al., 2010). This phenomenon, which was also reported for the other markers in the DTNBP1 locus and for other genes in complex genetic diseases, was termed the ‘Flip-Flop’ phenomenon (Lin et al., 2007) which can occur even without varying linkage disequilibrium between markers, e.g., due to haplotypic heterogeneity (Zaykin and Shibata, 2008).
The Dysbindin protein is a coiled-coil containing protein initially found in the muscle and the brain of mice to interact with alpha- and beta dystrobrevin (DTNA and DTNB) (Benson et al., 2001). DTNA and DTNB have been identified as members of the Dystrophin-associated protein complex (DPC) in the neuromuscular junction and the brain, which links the cytoskeleton to the extracellular matrix and scaffolds signaling protein (Benson et al., 2001, Veroni et al., 2007). While Dystrophin mutations cause several forms of X-linked muscular dystrophy, it seems important that Duchenne's muscular dystrophy in humans goes along with neuropsychological and neuropathological features reminiscent of schizophrenia (Harrison and Weinberger, 2005). More recently, in a Drosophila model that used an electrophysiology-based genetic screen to test the function of neuronal genes for a role in the homeostatic modulation of synaptic transmission, Dysbindin turned out to be essential for adaptive neural plasticity (Dickman and Davis, 2009). The authors concluded that Dysbindin may influence complex neurological diseases by alteration of homeostatic signaling (Dickman and Davis, 2009).
Recent data (Kubota et al., 2009) suggests an involvement of Dysbindin in the cytoskeletal organization of growth cones of hippocampal neurons. Reduced Dysbindin expression by RNA interference led to impaired neurite outgrowth and abnormal neurite morphology (Kubota et al., 2009). An impaired Dysbindin function seems to result in a failure of normal axon guidance by the disruption of growth cones during embryonic development, and therefore, in abnormal anatomical connectivity. Moreover, as shown by Kubota et al. (2009), Dysbindin hypofunctionality results in an aberrant organization of the actin cytoskeleton. These disturbances of cytoskeletal organization might lead not only to an abnormal thinning of neurites, but also to an abnormal enlargement.
The Dysbindin interactome has been shown to be complex and to involve a variety of proteins engaged in cytoskeletal anchoring and synaptic plasticity (Guo et al., 2009). Due to the different molecular environment in distinct neurons, Dysbindin hypofunctionality might lead to diverse effects on neurite morphology. Thus, the finding of both increased and decreased anatomic connectivity due to Dysbindin hypofunctionality seems plausible.
Given these biological functions of Dysbindin and the fact that Dysbindin variants have been shown to be associated with schizophrenia and cognitive function, it is plausible that genetic variation in Dysbindin might be involved in the pathogenesis of white matter alterations.
Diffusion tensor imaging (DTI) is an MRI-based imaging technique to assess white matter structures in a more detailed manner than conventional MRI (Beaulieu, 2002). DTI utilizes MR sequences sensitive to the diffusion movements of water molecules. Since the diffusion of water in brain tissue is limited by the coherence of the fiber tracts (Ono et al., 1995), structural fiber integrity, their diameter and packing density (Ono et al., 1995), and as well as by myelination (Gulani et al., 2001, Sakuma et al., 1991), proxy conclusions about white matter microstructure can be drawn from a DTI index called fractional anisotropy (FA) that quantitates how strongly directional the local tract structure is.
Whereas ROI-based or tractography analysis of DTI data sets requires an a priori-hypothesis, conventional VBM-style whole-brain approaches for multi-subject FA images have been criticized for alignment problems (Simon et al., 2005, Vangberg et al., 2006) and smoothing issues (Jones et al., 2005). The Tract-Based Spatial Statistics (TBSS) approach, however, tries to address both these problems by application of an initial approximate non-linear registration, followed by the projection of the FA values onto an alignment invariant tract representation, the “mean FA skeleton” (Smith et al., 2006). The mean FA skeleton is generated in a fully automatized procedure, in which first the voxels with the regionally highest FA values are identified and then the centers of the tracts are determined by local center-of-gravity (CofG) calculation.
Despite its obvious viability/optimization to studies of group difference in white matter structures there have only been four TBSS studies published in schizophrenia (Douaud et al., 2007, Karlsgodt et al., 2008, Miyata et al., 2009, Smith et al., 2006) and only two dealing with bipolar disorder (Benedetti et al., 2011, Versace et al., 2008). In general, studies dealing with schizophrenia found FA reductions in the callosal body and in the prefrontal regions in schizophrenia patients compared to healthy subjects.
In the current study we used TBSS in a genetic imaging study to correlate the rs1018381 variant in the Dysbindin gene with white matter changes in 83 healthy young individuals. MRI scans were performed and diffusion weighted image sequences were obtained. We hypothesized alterations of white matter tracts in carriers of the T-allele compared to C/C homozygotes in core regions of schizophrenia pathology such as the medial and superior temporal and the frontal lobes.
Section snippets
Subjects
The study protocol was approved by the local ethics committee of the University Hospital Aachen. Subjects were recruited from RWTH Aachen University students and by advertisements in local newspapers. The inclusion criteria were: age 18–55 years old, no psychiatric disorder according to ICD-10, and an absence of a family history for psychiatric disorders in first degree relatives. All subjects were of Western- or Middle European descent. 101 Subjects (74 men, 27 women) initially underwent
Demographics
The images of 83 subjects (62 males, 21 females) were included in our final TBSS analysis. The T allele carrier group consisted of 37 subjects (31 male, 6 female), the wild type group of 46 subjects (31 male, 15 female). Mean age in the T allele carrier group was 22.5 yrs (standard deviation: 2.2 yrs), in the wild type group 23.4 (standard deviation: 3.0 yrs). Both groups did not differ significantly in mean age (p = .18) or gender (p = .11).
Impact of the Dysbindin genotype on fiber tract integrity
We found two clusters of reduced FA values in Dysbindin
Discussion
In this study, we investigated the effects of the Dysbindin rs1018381 risk variant on fiber tract integrity of young healthy subjects without history of psychiatric disorders in first degree relatives. T-allele carriers showed two clusters of reduced FA values in the right perihippocampal region, and further exhibited six clusters of elevated FA values in the left frontal lobe, the right fornix, the right midbrain area, the left callosal body, the left cerebellum and in proximity of the right
Acknowledgment
We thank Prof. Dr. Simon B. Eickhoff (Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany) for his support of this study.
We furthermore acknowledge the help of Dr. Nicola Palomero Gallagher (Institute of Neuroscience and Medicine-1, Juelich Research Center, Juelich, Germany) with the manuscript.
T. N.-J., F.S. and U.H. received support by the International Research Training Group 1328. T.N.-J. was supported by domestic funding (“Rotationsstipendium”), RWTH Aachen
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