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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.
Affiliation
  • Hernandez LM; Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Lawrence KE; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Padgaonkar NT; Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Inada M; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Hoekstra JN; Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Lowe JK; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Eilbott J; Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Jack A; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Aylward E; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Gaab N; Autism & Neurodevelopmental Disorders Institute, The George Washington University, Washington, DC, USA.
  • Van Horn JD; Autism & Neurodevelopmental Disorders Institute, The George Washington University, Washington, DC, USA.
  • Bernier RA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
  • McPartland JC; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • Webb SJ; USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Laboratory of Neuro Imaging, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
  • Pelphrey KA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
  • Green SA; Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA.
  • Geschwind DH; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
  • Bookheimer SY; University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Dapretto M; Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Transl Psychiatry ; 10(1): 82, 2020 03 03.
Article in En | MEDLINE | ID: mdl-32127526
ABSTRACT
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.
Subject(s)

Full text: 1 Database: MEDLINE Main subject: Autism Spectrum Disorder Limits: Female / Humans / Male Language: En Year: 2020 Type: Article

Full text: 1 Database: MEDLINE Main subject: Autism Spectrum Disorder Limits: Female / Humans / Male Language: En Year: 2020 Type: Article