Genetic and Environmental Influences on Structural Brain Measures in Twins with Autism

Background: Atypical growth patterns of the brain have been reported in autism spectrum disorder (ASD) but these alterations are heterogeneous across individuals, which may be associated with the variable effects of genetic and environmental influences on the development of different brain structures.

Objectives: The primary objective of this investigation was to examine structural similarities and differences across the brain in twins with and without autism to determine whether variation in brain structure is associated with genetic or environmental factors in ASD.

Methods: Monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD (aged 6-15 years) participated in this study. T1-weighted MRIs were processed with FreeSurfer to evaluate structural brain measures. Intra-class correlations were examined within twin pairs and compared across groups. ACE modeling for broad sense heritability (a²= additive genetics) and environmental influences (c²= shared family environment, e²= unique environment) were calculated to provide an estimate of the proportion of variation associated with genetic and environmental factors. Pearson’s correlations of within twin pair differences in structural measures and symptom severity, as assessed with the Social Responsiveness Scale (SRS), were also examined to evaluate genetic and environmental influences on brain-behavior relationships.

Results: Good quality data were available for 164 twins [48 ASD twin pairs (19 MZ, 29 DZ); 34 TD twin pairs (20 MZ, 14 DZ)]. All structural brain measures that were assessed were best fit with either AE or CE models. Cerebral structure was primarily genetically-mediated in TD twins (a²= 0.60 – 0.89), except for global mean curvature (c²= 0.67 [0.41, 0.92) and cortical thickness of the temporal (a²= 0.33 [0.04, 0.63]) and occipital lobes (c²= 0.61 [0.45, 0.77). Cerebral structure was also predominantly genetically-mediated in twins with ASD (a²= 0.70 – 1.00); however, cerebellar white matter (WM) (c²= 0.48 [0.11, 0.85]) and frontal lobe grey matter (GM) volume (c²= 0.79 [0.63, 0.95]) as well as cortical thickness of the frontal (c²= 0.81 [0.71, 0.92]), temporal (c²= 0.77 [0.60, 0.93]), and parietal lobes (c²= 0.87 [0.77, 0.97]) were primarily associated with environmental factors. Conversely, occipital lobe thickness (a²= 0.93 [0.75, 1.11]) did not exhibit similar environmental influences in twins with ASD compared to TD controls. Twin pair differences in brain structure were also associated with differences in symptom severity, such as the relationships between social communication impairments (SRS) and GM volume of the frontal (r= 0.52 [0.18, 0.75]), temporal (r= 0.61 [0.30, 0.80]), and parietal lobes (r= 0.53 [0.19, 0.76]) in DZ twins with ASD.

Conclusions: Our findings suggest that environmental and genetic factors differentially affect brain structure in ASD. Although the majority of structural brain measures were primarily genetically-mediated in twins with ASD, it appeared that environmental factors may influence cerebellar WM and cortical thickness to a larger extent, with a more pervasive pattern compared to TD controls. Future studies should examine the periods of increased susceptibility to environmental factors and track changes in neurobiological profiles in relation to symptom presentation to increase the potential for neurobiological stratification in the future.