‘Reading the Mind in the Eyes': Phenotypic and Endophenotypic Associations in Males and Females with Autism

Background:  Atypical social cognitive processing is a hallmark of autism spectrum conditions (ASC), and a potential endophenotype for ASC. Endophenotypes are heritable components associated with increased risk for a condition that are apparent in family members at a higher rate than the general population, independent of whether the family member has the condition or not (Gottesman & Gould, 2003). Differences in performance and neural activation on the ‘Reading the Mind in the Eyes’ (Eyes task) have been identified in individuals with ASC compared to neurotypical individuals in previous studies.  

Objectives:  This study aimed to examine group differences (ASC vs. controls and siblings vs. controls) in performance and neural activation on the Eyes task, to establish whether they are potential phenotypic or endophenotypic markers for autism. 

Methods:  Performance on the Eyes task and the associated neural activation was examined in adolescents (aged 12-18 years) with ASC (N=50), their unaffected related siblings (N=40) and typically developing controls (N=40). Because the prior literature suggests that males and females with ASC may display different cognitive and associated neural characteristics, analyses were stratified by sex. Three strategies were applied to test for endophenotype at the level of neural activation: (1) identifying and locating conjunctions of ASC-control and sibling-control differences; (2) examining whether the sibling group is comparable to the ASC or intermediate between the ASC and control groups; and (3) examining spatial overlaps between ASC-control and sibling-control differences across multiple thresholds.

Results:  Performance differences on the task were observed in male participants (F(2, 61)=3.39, p=0.04), where impaired performance on the Eyes task was observed in the ASC compared to the control groups (p=0.016). In females, only trend level group differences were observed between the ASC and control groups (p=0.051). In either sex, no performance difference was identified between sibling and same-sex control groups. In males, task-related increase in neural activation was observed in the control compared to the ASC groups in a left lateralized cluster (FDR q=0.004; cluster size Ke=2263; peak-coordinate MNI=-36, 36, -8) involving the inferior prefrontal cortex, orbitofrontal, temporopolar and middle temporal gyrus. In females there was also significantly greater activation in the control compared to the ASC groups  in a cluster (FDR q=0.017; Ke=2661; peak-coordinate MNI=14 24 6) involving bilateral inferior prefrontal gyrus, left orbitofrontal and left anterior prefrontal cortex. Most importantly, neural activation showed a significant and substantial endophenotypic effect in the female groups (in the direction of [control>ASC AND control>siblings]), but only modest in the male groups. 

Conclusions: Behavioural impairment on complex emotion recognition associated with mental state attribution is a phenotypic, rather than endophenotypic marker of ASC. The neural response to the Eyes task may serve as a potential endophenotypic marker for ASC, particularly in females. These findings contribute to the understanding of the neural mechanism underlying social cognition in autism, indicating a possible genetic basis to the associated neural response.