Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2

Abstract

Recent genetic studies have implicated a number of candidate genes in the pathogenesis of Autism Spectrum Disorder (ASD). Polymorphisms of CNTNAP2 (contactin-associated like protein-2), a member of the neurexin family, have already been implicated as a susceptibility gene for autism by at least 3 separate studies. We investigated variation in white and grey matter morphology using structural MRI and diffusion tensor imaging. We compared volumetric differences in white and grey matter and fractional anisotropy values in control subjects characterised by genotype at rs7794745, a single nucleotide polymorphism in CNTNAP2. Homozygotes for the risk allele showed significant reductions in grey and white matter volume and fractional anisotropy in several regions that have already been implicated in ASD, including the cerebellum, fusiform gyrus, occipital and frontal cortices. Male homozygotes for the risk alleles showed greater reductions in grey matter in the right frontal pole and in FA in the right rostral fronto-occipital fasciculus compared to their female counterparts who showed greater reductions in FA of the anterior thalamic radiation. Thus a risk allele for autism results in significant cerebral morphological variation, despite the absence of overt symptoms or behavioural abnormalities. The results are consistent with accumulating evidence of CNTNAP2's function in neuronal development. The finding suggests the possibility that the heterogeneous manifestations of ASD can be aetiologically characterised into distinct subtypes through genetic-morphological analysis.

Fig. 1

Reductions in GM volume, WM volume and FA in risk homozygotes compared to carriers and major allele homozygotes in the occipital lobe. Thresholded t-statistics are shown in red for GM, green for WM and blue for FA and overlaid on the warped average of each T1-MDEFT and on the MNI-DTI template.

Fig. 2

Reductions in GM volume, WM volume and FA in risk homozygotes compared to carriers and major allele homozygotes in the cerebellum. Thresholded t-statistics are shown in red for GM, green for WM and blue for FA and overlaid on the warped average of each T1-MDEFT and on the MNI-DTI template.

Fig. 3

Reductions in GM volume, WM volume and FA in risk homozygotes compared to carriers and major allele homozygotes in the frontal lobe. Thresholded t-statistics are shown in red for GM, green for WM and blue for FA and overlaid on the warped average of each T1-MDEFT and on the MNI-DTI template.

Fig. 4

Male–female sex interaction for reduced GM volume in the right frontal pole. Thresholded t-statistics are shown and overlaid on the warped average of each T1-MDEFT. The plot shows that both male and female risk homozygotes have a significant GM volume reduction compared to their same sex carriers and major homozygotes in this region, but that the reduction observed in males is significantly larger than that seen in females. Black bars are 95% confidence.

Fig. 5

Male–female sex interaction for reduction in FA. Thresholded t-statistics are overlaid on the MNI-DTI template and the warped average of each T1-MDEFT. Areas of reduction in risk homozygotes compared to carriers and major allele homozygotes are shown in blue in females and in red in males. Areas significantly more reduced in females than in males are shown in cyan, while those more reduced in males than in females are shown in yellow.