TY - JOUR
T1 - Imaging-genetics of sex differences in ASD
T2 - distinct effects of OXTR variants on brain connectivity
AU - On behalf of the GENDAAR Consortium
AU - Hernandez, Leanna M.
AU - Lawrence, Katherine E.
AU - Padgaonkar, N. Tanya
AU - Inada, Marisa
AU - Hoekstra, Jackson N.
AU - Lowe, Jennifer K.
AU - Eilbott, Jeffrey
AU - Jack, Allison
AU - Aylward, Elizabeth
AU - Gaab, Nadine
AU - Van Horn, John D.
AU - Bernier, Raphael A.
AU - McPartland, James C.
AU - Webb, Sara J.
AU - Pelphrey, Kevin A.
AU - Green, Shulamite A.
AU - Geschwind, Daniel H.
AU - Bookheimer, Susan Y.
AU - Dapretto, Mirella
N1 - Funding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke (award number F99NS105206 to L.M.H.), the National Institute of Mental Health (award numbers R01MH100028 to K.A.P., F31MH110140 to K.E.L., and F32MH105167 to S.A.G.), the National Science Foundation (Graduate Research Fellowship award number 1650604 to N.T.P.), and the ARCS Foundation. We are also grateful for generous support from the Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson-Lovelace Foundation, The Ahmanson Foundation, Capital Group Companies Charitable Foundation, William M. and Linda R. Dietel Philanthropic Fund, and Northstar Fund. Research reported in this publication was also partially supported by the National Center for Research Resources and by the Office of the Director of the National Institutes of Health under award numbers C06RR012169, C06RR015431, and S10OD011939. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41398-020-0750-9
DO - 10.1038/s41398-020-0750-9
M3 - Article
C2 - 32127526
AN - SCOPUS:85081042241
SN - 2158-3188
VL - 10
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 82
ER -