title: 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 and schizophrenia, 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.
authors.affiliation: Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA. clemm@bwh.harvard.edu
authors.forename: Christian
authors.initials: C
authors.lastname: Clemm von Hohenberg
authors.forename: Marlene C
authors.initials: MC
authors.lastname: Wigand
authors.forename: Marek
authors.initials: M
authors.lastname: Kubicki
authors.forename: Gregor
authors.initials: G
authors.lastname: Leicht
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: Susanne
authors.initials: S
authors.lastname: Karch
authors.forename: Annette M
authors.initials: AM
authors.lastname: Hartmann
authors.forename: Bettina
authors.initials: B
authors.lastname: Konte
authors.forename: Marion
authors.initials: M
authors.lastname: Friedl
authors.forename: Thomas
authors.initials: T
authors.lastname: Ballinger
authors.forename: Ryan
authors.initials: R
authors.lastname: Eckbo
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bouix
authors.forename: Lorenz
authors.initials: L
authors.lastname: Jäger
authors.forename: Martha E
authors.initials: ME
authors.lastname: Shenton
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Christoph
authors.initials: C
authors.lastname: Mulert
mesh_terms: D000328:Adult; D016880:Anisotropy; D001921:Brain / Q000473:pathology*; D004252:DNA Mutational Analysis; D056324:Diffusion Tensor Imaging; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology*; D018709:Statistics, Nonparametric
chemical_list: C403049:CNTNAP2 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins
keywords: Autism; Caspr2; Endophenotype; Genetics; Magnetic resonance imaging; Schizophrenia