A Twin Study of Altered White Matter Heritability in Youth With Autism Spectrum Disorder

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Hegarty, J. P., Monterrey, J. C., Tian, Q., Cleveland, S. C., Gong, X., Phillips, J. M., Wolke, O. N., McNab, J. A., Hallmayer, J. F., Reiss, A. L., Hardan, A. Y., & Lazzeroni, L. C. (2023). A Twin Study of Altered White Matter Heritability in Youth With Autism Spectrum Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 63(1), 65-79. https://doi.org/10.1016/j.jaac.2023.05.030

Publication date: 3 Jul 2023 Added to AutiHub: 5 Oct 2026 Type: Article Article language: English
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Authors

Publication authors
12
Publication authors identified as autistic
1 / 12 (8.3%)
  1. John P. Hegarty *
  2. Julio C Monterrey
  3. Qiyuan Tian
  4. Sue C. Cleveland
  1. Xinyi Gong
  2. Jennifer M. Phillips
  3. Olga N. Wolke
  4. Jennifer A. McNab
  1. Joachim F. Hallmayer
  2. Allan L. Reiss
  3. Antonio Y. Hardan
  4. Laura C. Lazzeroni

Abstract

OBJECTIVE: White matter alterations are frequently reported in autism spectrum disorder (ASD), yet the etiology is currently unknown. The objective of this investigation was to examine, for the first time, the impact of genetic and environmental factors on white matter microstructure in twins with ASD compared to control twins without ASD. METHOD: Diffusion-weighted MRIs were obtained from same-sex twin pairs (6-15 years of age) in which at least 1 twin was diagnosed with ASD or neither twin exhibited a history of neurological or psychiatric disorders. Fractional anisotropy (FA) and mean diffusivity (MD) were examined across different white matter tracts in the brain, and statistical and twin modeling were completed to assess the proportion of variation associated with additive genetic (A) and common/shared (C) or unique (E) environmental factors. We also developed a novel Twin-Pair Difference Score analysis method that produces quantitative estimates of the genetic and environmental contributions to shared covariance between different brain and behavioral traits. RESULTS: Good-quality data were available from 84 twin pairs, 50 ASD pairs (32 concordant for ASD [16 monozygotic; 16 dizygotic], 16 discordant for ASD [3 monozygotic; 13 dizygotic], and 2 pairs in which 1 twin had ASD and the other exhibited some subthreshold symptoms [1 monozygotic; 1 dizygotic]) and 34 control pairs (20 monozygotic; 14 dizygotic). Average FA and MD across the brain, respectively, were primarily genetically mediated in both control twins (A = 0.80, 95% CI [0.57, 1.02]; A = 0.80 [0.55, 1.04]) and twins concordant for having ASD (A = 0.71 [0.33, 1.09]; A = 0.84 [0.32,1.36]). However, there were also significant tract-specific differences between groups. For instance, genetic effects on commissural fibers were primarily associated with differences in general cognitive abilities and perhaps some diagnostic differences for ASD because Twin-Pair Difference-Score analysis indicated that genetic factors may have contributed to ∼40% to 50% of the covariation between IQ scores and FA of the corpus callosum. Conversely, the increased impact of environmental factors on some projection and association fibers were primarily associated with differences in symptom severity in twins with ASD; for example, our analyses suggested that unique environmental factors may have contributed to ∼10% to 20% of the covariation between autism-related symptom severity and FA of the cerebellar peduncles and external capsule. CONCLUSION: White matter alterations in youth with ASD are associated with both genetic contributions and potentially increased vulnerability or responsivity to environmental influences. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as living with a disability. The author list of this paper includes contributors from the location and/or community where the research was conducted and they participated in the data collection, design, analysis, and/or interpretation of the work.

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Cited references
65
With a DOI
60
Without a DOI, from raw bibliography text
5
4 / 65 (6.2%) cited references include at least one author identified as autistic.
References with data to complete
3 / 65 (4.6%)
References with detected author names
62 / 65 (95.4%)
Without detected author names
3
Without a structured title
1
Without a stable identifier
5
References with raw author names still to review
1
References with external metadata lookup issues
0
These indicators apply to cited references displayed on this page, after technical duplicates have been merged. A reference without a DOI can still support author statistics when a title and author names are available.
Author names detected in the cited bibliography
435
From DOI or external metadata
435
From validated raw bibliography text
0
Raw names already validated
0
Raw names still to review
1
88 / 435 (20.2%) names are linked to an author already present in AutiHub. 347 / 435 (79.8%) names are not yet linked.
Names linked to a person identified as autistic
4 / 435 (0.9%)
Calculated across all author names detected in the cited bibliography. Among names linked to an author already present in AutiHub: 4 / 88 (4.5%). Distinct people identified as autistic: 1 / 343 (0.3%).
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