A translational exploration of the effects of WNT2 variants on altered cortical structures in autism spectrum disorder

Yi-Ling Chien, Yu-Chieh Chen, Yen-Nan Chiu, Wen-Che Tsai, Susan Shur-Fen Gau, Yi-Ling Chien, Yu-Chieh Chen, Yen-Nan Chiu, Wen-Che Tsai, Susan Shur-Fen Gau

Abstract

Background: Evidence suggests that cortical anatomy may be aytpical in autism spectrum disorder. The wingless-type MMTV integration site family, member 2 (WNT2), a candidate gene for autism spectrum disorder, may regulate cortical development. However, it is unclear whether WNT2 variants are associated with altered cortical thickness in autism spectrum disorder.

Methods: In a sample of 118 people with autism spectrum disorder and 122 typically developing controls, we investigated cortical thickness using FreeSurfer software. We then examined the main effects of the WNT2 variants and the interactions of group × SNP and age × SNP for each hemisphere and brain region that was altered in people with autism spectrum disorder.

Results: Compared to neurotypical controls, people with autism spectrum disorder showed reduced mean cortical thickness in both hemispheres and 9 cortical regions after false discovery rate correction, including the right cingulate gyrus, the orbital gyrus, the insula, the inferior frontal gyrus (orbital part and triangular part), the lateral occipitotemporal gyrus, the posterior transverse collateral sulcus, the lateral sulcus and the superior temporal sulcus. In the full sample, 2 SNPs of WNT2 (rs6950765 and rs2896218) showed age × SNP interactions for the mean cortical thickness of both hemispheres, the middle-posterior cingulate cortex and the superior temporal cortex.

Limitations: We examined the genetic effect for each hemisphere and the 9 regions that were altered in autism spectrum disorder. The age effect we found in this cross-sectional study needs to be examined in longitudinal studies.

Conclusion: Based on neuroimaging and genetic data, our findings suggest that WNT2 variants might be associated with altered cortical thickness in autism spectrum disorder. Whether and how these WNT2 variants might involve cortical thinning requires further investigation.

Trial registration: ClinicalTrials.gov no. NCT01582256.

Protocol registration: National Institutes of Health no. NCT00494754.

Conflict of interest statement

Competing interests: None declared.

© 2021 CMA Joule Inc. or its licensors.

Figures

Figure 1
Figure 1
The 9 cortical regions identified with reduced cortical thickness, presented on (A) a standard brain cortex and (B) an inflated brain cortex.
Figure 2
Figure 2
The genotypes rs6950765 and rs2896218 were associated with mean cortical thickness in both hemispheres. (A) Genotype rs6950765 and the mean thickness of the left hemisphere. (B) Genotype rs6950765 and the mean thickness of the right hemisphere. (C) Genotype rs2896218 and the mean thickness of the left hemisphere. (D) Genotype rs2896218 and the mean thickness of the right hemisphere. The CG of rs6950765 and the AG of rs2896218 showed greater cortical thinning of both hemispheres with age.

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