Altered Structural Brain Connectivity in Healthy Carriers of the Autism Risk Gene,CNTNAP2

Abstract

Recently, carriers of a common variant in the autism risk gene, CNTNAP2, were found to have altered functional brain connectivity using functional MRI. Here we scanned 328 young adults with high-field (4-Tesla) diffusion imaging, to test the hypothesis that carriers of this gene variant would have altered structural brain connectivity. All participants (209 females, 119 males, age: 23.4 +/−2.17 SD years) were scanned with 105-gradient high angular diffusion imaging (HARDI) at 4 Tesla. After performing a whole-brain fiber tractography using the full angular resolution of the diffusion scans, 70 cortical surface-based regions of interest were created from each individual’s co-registered anatomical data to compute graph metrics for all pairs of cortical regions. In graph theory analyses, subjects homozygous for the risk allele (CC) had lower characteristic path length, greater small-worldness and global efficiency in whole brain analyses, as well as greater eccentricity (maximum path length) in 60 of 70 nodes in regional analyses. These results were not reducible to differences in more commonly studied traits such as fiber density or fractional anisotropy. This is the first study to link graph theory metrics of brain structural connectivity to a common genetic variant linked with autism and will help us understand the neurobiology of circuits implicated in risk for autism.

Shining a light on CNTNAP2: complex functions to complex disorders

“…Imaging genetics has also implicated SNPs that were previously associated with autism (rs7794745 and rs2710102), and SLI, dyslexia, and communication in normal cohorts (rs2710102). [29][30][31][32] Carrying a 'risk' allele at these loci seems to correlate with altered structural and functional imaging measures. It has been suggested that the effects on structural and functional brain networks seen in individuals carrying these risk variants may underlie their association with disorders such as autism, SLI and schizophrenia.…”

Breakdown of Brain Connectivity Between Normal Aging and Alzheimer's Disease: A Structuralk-Core Network Analysis

“…Many analyses of brain connectivity have been conducted in this way (Dennis et al, 2012a, b;Dennis and Thompson, 2012;Jahanshad et al, 2011Jahanshad et al, , 2012Zalesky, 2009;Zhan et al, 2012). Connectivity matrices were compiled using a processing pipeline described previously (Braskie et al, 2012a, b;Dennis et al, 2012b;Jahanshad et al, 2011Jahanshad et al, , 2012Nir et al, 2012a, b).…”

Micro-, Meso- and Macro-Connectomics of the Brain

“…Candidate gene analyses have even suggested that connectome properties may be associated with genetic risk factors for diseases and disorders such as autism (Scott-Van Zeeland et al 2010;Dennis et al 2011), schizophrenia (Braskie et al 2012), and dementia Jahanshad et al 2012); given the history of candidate gene associations in psychiatric genetics, these findings will need to be replicated Fig. 1 Various forms of connectivity measures extracted from brain images; all these methods allow us to study the brain from a higher dimensional perspective and observe correlations and connections between regions.…”