CNTNAP2 polymorphisms and structural brain connectivity: A diffusion-tensor imaging study

Abstract

CNTNAP2 is a gene on chromosome 7 that has shown associations with autism andschizophrenia, and there is evidence that it plays an important role for neuronal synchronization and brain connectivity. In this study, we assessed the relationship between Diffusion Tensor Imaging (DTI), a putative marker of anatomical brain connectivity, and multiple single nucleotide polymorphisms (SNPs) spread out over this large gene. 81 healthy controls and 44 patients with schizophrenia (all Caucasian) underwent DTI and genotyping of 31 SNPs within CNTNAP2. We employed Tract-based Spatial Statistics (TBSS) for inter-subject brain registration and computed average diffusivity values for six major white matter tracts. Analyses of Covariance (ANCOVAs) were computed to test for possible associations with genotypes. The strongest association, which survived rigorous Bonferroni correction, was between rs2710126 genotype and Fractional Anisotropy (FA) in the uncinate fasciculus (p=.00003). This anatomical location is particularly interesting given the enriched fronto-temporal expression of CNTNAP2 in the developing brain. For this SNP, no phenotype association has been reported before. There were several further genotype-DTI associations that were nominally significant but did not survive Bonferroni correction, including an association between axial diffusivity in the dorsal cingulum bundle and a region in intron 13 (represented by rs2710102, rs759178, rs2538991), which has previously been reported to be associated with anterior-posterior functional connectivity. We present new evidence about the effects of CNTNAP2 on brain connectivity, whose disruption has been hypothesized to be central to schizophrenia pathophysiology.