A common variant of the CNTNAP2 gene is associated with structural variation in the left superior occipital gyrus

Abstract

a b s t r a c tThe CNTNAP2 gene encodes a cell-adhesion molecule that influences the properties of neural networks and the morphology and density of neurons and glial cells. Previous studies have shown association of CNTNAP2 variants with language-related phenotypes in health and disease. Here, we report associations of a common CNTNAP2 polymorphism (rs7794745) with variation in grey matter in a region in the dorsal visual stream. We tried to replicate an earlier study on 314 subjects by Tan et al. (2010), but now in a substantially larger group of more than 1700 subjects. Carriers of the T allele showed reduced grey matter volume in left superior occipital gyrus, while we did not replicate associations with grey matter volume in other regions identified by Tan et al. (2010). Our work illustrates the importance of independent replication in neuroimaging genetic studies of language-related candidate genes.

Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review

“…With respect to brain structure, two studies have identified regional reductions in gray matter volume associated with the risk allele on rs7794745 primarily affecting occipital, fusiform, and cerebellar regions (Tan, Doke, Ashburner, Wood, & Frackowiak, ; Uddén, Snijders, Fisher, & Hagoort, ). Additionally, altered white matter structure associated with CNTNAP2 has been reported in fronto‐occipital and thalamic tracts (Tan et al, ) as well as midbrain tracts that facilitate communication among the cortex, cerebellum, and other central nervous system structures (Skeide et al, ).…”

“…Further, these authors observed an interaction between lateralization of function during voice processing (forward and reversed speech), rs7794745 genotype, and handedness, suggesting a complex influence of this SNP on voice processing networks in relation to handedness and lateralization. 6 With respect to brain structure, two studies have identified regional reductions in gray matter volume associated with the risk allele on rs7794745 primarily affecting occipital, fusiform, and cerebellar regions (Tan, Doke, Ashburner, Wood, & Frackowiak, 2010;Uddén, Snijders, Fisher, & Hagoort, 2017). Additionally, altered white matter structure associated with CNTNAP2 has been reported in fronto-occipital and thalamic tracts (Tan et al, 2010) as well as midbrain tracts that facilitate communication among the cortex, cerebellum, and other central nervous system structures (Skeide et al, 2016).…”

“…Imaging genetics studies of FOXP2 indicate that this gene affects brain regions associated with language production and speech motor planning (Liegeois et al, 2003;Pinel et al, 2012;Vargha-Khadem, Gadian, Copp, & Mishkin, 2005), with preliminary links to activity in posterior language regions (Wilcke et al, 2012). CNTNAP2 has also been found to have effects on functional activation in languagerelated regions, including inferior frontal and middle temporal gyri (Whalley et al, 2011) and on gray matter morphology in occipital, fusiform, and cerebellar regions (Tan et al, 2010;Uddén et al, 2017); in addition, this gene has effects on structural and functional connectivity among language-associated regions and more domain general regions (Dennis et al, 2011;Skeide et al, 2016). The compelling neuroimaging genetic findings related to both of these genes may direct future research to further characterize their roles in DLD.…”

Comprehensive cross-disorder analyses of CNTNAP2 suggest it is unlikely to be a primary risk gene for psychiatric disorders

“…Neuroimaging studies have supported the notion that these common variants play a role in psychiatric disorders. SNP rs2710102 has been implicated in brain connectivity in healthy individuals [16, 18, 19], and rs7794745 was implicated in audio-visual speech perception [69], voice-specific brain function [22], and was associated with reduced grey matter volume in left superior occipital gyrus [20, 21]. These studies focused principally on language tasks in general population, given the reported suggestive implications of CNTNAP2 in language impairment traits of ASD or language-related phenotypes.…”

“…Moreover, in subsequent studies, rs2710102 was implicated in early language acquisition in the general population [15], and showed functional effects on brain activation in neuroimaging studies [16-19]. Furthermore, genotypes at rs7794745 were associated with reduced grey matter volume in the left superior occipital gyrus in two independent studies [20, 21], and alleles of this SNP were reported to affect voice-specific brain function [22]. Genetic associations with ASD for these, and several other SNPs in CNTNAP2 , have been reported in a number of studies [23-28].…”