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Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity

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...

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Autores principales: Hernandez, Leanna M., Lawrence, Katherine E., Padgaonkar, N. Tanya, Inada, Marisa, Hoekstra, Jackson N., Lowe, Jennifer K., Eilbott, Jeffrey, Jack, Allison, Aylward, Elizabeth, Gaab, Nadine, Van Horn, John D., Bernier, Raphael A., McPartland, James C., Webb, Sara J., Pelphrey, Kevin A., Green, Shulamite A., Geschwind, Daniel H., Bookheimer, Susan Y., Dapretto, Mirella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054353/
https://www.ncbi.nlm.nih.gov/pubmed/32127526
http://dx.doi.org/10.1038/s41398-020-0750-9
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author Hernandez, Leanna M.
Lawrence, Katherine E.
Padgaonkar, N. Tanya
Inada, Marisa
Hoekstra, Jackson N.
Lowe, Jennifer K.
Eilbott, Jeffrey
Jack, Allison
Aylward, Elizabeth
Gaab, Nadine
Van Horn, John D.
Bernier, Raphael A.
McPartland, James C.
Webb, Sara J.
Pelphrey, Kevin A.
Green, Shulamite A.
Geschwind, Daniel H.
Bookheimer, Susan Y.
Dapretto, Mirella
author_facet Hernandez, Leanna M.
Lawrence, Katherine E.
Padgaonkar, N. Tanya
Inada, Marisa
Hoekstra, Jackson N.
Lowe, Jennifer K.
Eilbott, Jeffrey
Jack, Allison
Aylward, Elizabeth
Gaab, Nadine
Van Horn, John D.
Bernier, Raphael A.
McPartland, James C.
Webb, Sara J.
Pelphrey, Kevin A.
Green, Shulamite A.
Geschwind, Daniel H.
Bookheimer, Susan Y.
Dapretto, Mirella
author_sort Hernandez, Leanna M.
collection PubMed
description 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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spelling pubmed-70543532020-03-19 Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity Hernandez, Leanna M. Lawrence, Katherine E. Padgaonkar, N. Tanya Inada, Marisa Hoekstra, Jackson N. Lowe, Jennifer K. Eilbott, Jeffrey Jack, Allison Aylward, Elizabeth Gaab, Nadine Van Horn, John D. Bernier, Raphael A. McPartland, James C. Webb, Sara J. Pelphrey, Kevin A. Green, Shulamite A. Geschwind, Daniel H. Bookheimer, Susan Y. Dapretto, Mirella Transl Psychiatry Article 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. Nature Publishing Group UK 2020-03-03 /pmc/articles/PMC7054353/ /pubmed/32127526 http://dx.doi.org/10.1038/s41398-020-0750-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hernandez, Leanna M.
Lawrence, Katherine E.
Padgaonkar, N. Tanya
Inada, Marisa
Hoekstra, Jackson N.
Lowe, Jennifer K.
Eilbott, Jeffrey
Jack, Allison
Aylward, Elizabeth
Gaab, Nadine
Van Horn, John D.
Bernier, Raphael A.
McPartland, James C.
Webb, Sara J.
Pelphrey, Kevin A.
Green, Shulamite A.
Geschwind, Daniel H.
Bookheimer, Susan Y.
Dapretto, Mirella
Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity
title Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity
title_full Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity
title_fullStr Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity
title_full_unstemmed Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity
title_short Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity
title_sort imaging-genetics of sex differences in asd: distinct effects of oxtr variants on brain connectivity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054353/
https://www.ncbi.nlm.nih.gov/pubmed/32127526
http://dx.doi.org/10.1038/s41398-020-0750-9
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