Associations Between the EFHC2 Gene and Male Vulnerability to Impaired Social Cognition

Background: Autism Spectrum Disorders (ASDs), which are characterised by impaired social cognition, occur more commonly in males than females. Reasons behind the sex difference of an increased male vulnerability to impaired social cognition are unknown, although genes on the X chromosome have been suggested to play a role as males possess one copy of this chromosome while females possess two. Using Turner Syndrome (TS, X-monosomy) women to investigate genes on the X chromosome which affect social cognition we have identified an influence of SNP rs7055196 in the X-linked EFHC2 gene; women possessing the rare G allele (8.8%) showed poorer facial fear recognition than women possessing the common A allele. We have recently extended this work to neurotypical males (also X-monosomic), finding that G allele males also show poorer facial fear recognition accuracy than A allele males. Further, G allele males performed poorer on the Reading the Mind in the Eyes task (RMET) compared to A allele males; this is a theory of mind task which consists of a series of images of the eye region and participants are required to identify the mental state portrayed. ASD individuals also perform poorer and show differences in brain activity in regions of the social brain during the RMET compared to controls. This suggests there may be similarities between ASD males and neurotypical males possessing the rare G allele at SNP rs7055196 in terms of performance and neural activity during the RMET.

Objectives: We compared neural activity during a modified version of the RMET between high functioning ASD males and neurotypical males possessing the A and G alleles at SNP rs7055196.

Methods: Using an fMRI paradigm, we recorded neural activations of high functioning ASD males, neurotypical males possessing the A allele at SNP rs7055196 and neurotypical males possessing the G allele at SNP rs7055196 during a modified version of the RMET. This version of the task consisted of the original task along with a comparison task in which participants were asked to judge the age of the person in the images. The three groups were matched for age and IQ, and activations compared across groups.

Results: ASD males and neurotypical males possessing the rare G variant at SNP rs7055196 show similarities in neural activations of regions in the social brain during the modified RMET. In comparison, neural activations for both of these groups differ from those produced by neurotypical males possessing the common A allele at SNP rs7055196.

Conclusions: Our results suggest an association between theory of mind abilities and the EFHC2 gene. The location of this gene on the X chromosome supports a role for X-linked genes in contributing towards the sex difference in impaired social cognition, helping to explain why males are more vulnerable to ASDs compared to females. Further, this work suggests variation within the EFHC2 gene may contribute towards the development of autistic traits, and this gene is a prime candidate gene for further investigation into genetic contributions towards these traits.