John P. Hegarty II, PhD; Laura C. Lazzeroni, PhD; Mira M. Raman, MD; Joachim F. Hallmayer, MD; Sue C. Cleveland, BS; Olga N. Wolke, MD; Jennifer M. Phillips, PhD; Allan L. Reiss, MD; Antonio Y. Hardan, MD
Background: Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs.
Methods: We obtained T1-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6–15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a2 = additive genetics; c2 = common or shared environment; e2 = unique or nonshared environment). We also assessed correlations with RRB severity.
Results: Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a2 = 0.56 to 0.87), except for ACC white matter volume (a2 = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a2 = 0.65 to 0.97), but the cortical thickness of the ACC (c2 = 0.44, 95% CI 0.22 to 0.66) and OFC (c2 = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated.
Limitations: We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors.
Conclusion: Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD.
Submitted Feb. 12, 2019; Revised Apr. 2, 2019; Accepted June 10, 2019; Published online Oct. 11, 2019
Acknowledgements: The authors thank the participants and their families, many of whom travelled great distances, for their involvement in this research.
Affiliations: From the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA (Hegarty, Lazzeroni, Raman, Hallmayer, Cleveland, Phillips, Reiss, Hardan); the Department of Biomedical Data Science, Stanford University, Stanford, CA (Lazzeroni); and the Department of Anesthesiology, Stanford University, Stanford, CA (Wolke).
Funding: This work was supported by a grant from the National Institute of Mental Health (R01MH083972 to A.Y.H.), and J. Hegarty was supported by the Bass Society Pediatric Fellowship Program. These funding sources had no involvement in this research, and the authors have no conflicts of interest to declare.
Competing interests: None declared.
Contributors: L. Lazzeroni, J. Hallmayer, A. Reiss and A. Hardan designed the study. J. Hegarty, M. Raman, S. Cleveland, O. Wolke, J. Phillips, A. Reiss and A. Hardan acquired the data, which J. Hegarty, L. Lazzeroni, M. Raman and A. Hardan analyzed. J. Hegarty and A. Hardan wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Correspondence to: J. Hegarty, Autism and Developmental Disorders Research Program, Department of Psychiatry and Behavioral Sciences, Stanford University, School of Medicine, 401 Quarry Rd, Stanford, CA 94305; firstname.lastname@example.org