Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity
Open accessAbstract
Autism spectrum disorder (ASD) is more prevalent in males than in females, but the neurobiological mechanisms that give rise to this sex-bias are poorly understood. The female protective hypothesis suggests that the manifestation of ASD in females requires higher cumulative genetic and environmental risk relative to males. Here, we test this hypothesis by assessing the additive impact of several ASD-associated OXTR variants on reward network resting-state functional connectivity in males and females with and without ASD, and explore how genotype, sex, and diagnosis relate to heterogeneity in neuroendophenotypes. Females with ASD who carried a greater number of ASD-associated risk alleles in the OXTR gene showed greater functional connectivity between the nucleus accumbens (NAcc; hub of the reward network) and subcortical brain areas important for motor learning. Relative to males with ASD, females with ASD and higher OXTR risk-allele-dosage showed increased connectivity between the NAcc, subcortical regions, and prefrontal brain areas involved in mentalizing. This increased connectivity between NAcc and prefrontal cortex mirrored the relationship between genetic risk and brain connectivity observed in neurotypical males showing that, under increased OXTR genetic risk load, females with ASD and neurotypical males displayed increased connectivity between reward-related brain regions and prefrontal cortex. These results indicate that females with ASD differentially modulate the effects of increased genetic risk on brain connectivity relative to males with ASD, providing new insights into the neurobiological mechanisms through which the female protective effect may manifest.
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Polymorphisms in OXTR contribute to sexually dimorphic alterations in functional connectivity between the NAc and PFC.
“Polymorphisms in OXTR also contribute to sexually dimorphic alterations in functional connectivity between the NAc and PFC [35,36].”
From Translational opportunities for circuit-based social neuroscience: advancing 21st century psychiatry (2021) · cites this paper as [35]
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- Authors
- Hernandez, L. M., Lawrence, K. E., Padgaonkar, N. T., Inada, M., Hoekstra, J. N., Lowe, J. K., Eilbott, J., Jack, A., Aylward, E., Gaab, N., Van Horn, J. D., Bernier, R. A., McPartland, J. C., Webb, S. J., Pelphrey, K. A., Green, S. A., Geschwind, D. H., Bookheimer, S. Y., Dapretto, M., & On behalf of the GENDAAR Consortium
- Affiliations
- University of California, Los Angeles (US)
- George Washington University (US)
- Seattle Children's Research Institute (US)
- Harvard University (US)
- University of Washington (US)
- Yale University (US)
- University of Virginia (US)
- Corresponding author
- Dapretto, Mirella
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2020-03-03
- Volume
- 10
- Issue
- 1
- Pages
- 82-82
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC7054353
- OpenAlex
- W3010132840
- Cited by
- 54
- References
- 71
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 6 · 2023: 11 · 2022: 6 · 2021: 13 · 2020: 6
- FWCI
- 4.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (F99NS105206)
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (F31MH110140, R01MH100028, F32MH105167)
- ARCS Foundation
- National Science Foundation (1650604)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Keywords
- autism spectrum disorder, sex differences, oxytocin receptor, reward network, resting-state functional connectivity, nucleus accumbens, prefrontal cortex, subcortical structures, risk alleles, brain connectivity
- MeSH terms
- Autism Spectrum Disorder, Brain, Brain Mapping, Female, Humans, Magnetic Resonance Imaging, Male, Neural Pathways, Reward, Sex Characteristics, Receptors, Oxytocin
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