Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect

Katherine E. Lawrence, Leanna M. Hernandez, Emily Fuster, Namita T. Padgaonkar, Genevieve Patterson, Jiwon Jung, Nana J. Okada, Jennifer K. Lowe, Jackson N. Hoekstra, Allison Jack, Elizabeth Aylward, Nadine Gaab, John D. Van Horn, Raphael A. Bernier, James C. McPartland, Sara J. Webb, Kevin A. Pelphrey, Shulamite A. Green, Susan Y. Bookheimer, Daniel H. GeschwindMirella Dapretto, Elizabeth Aylward, Raphael A. Bernier, Susan Y. Bookheimer, Mirella Dapretto, Nadine Gaab, Allison Jack, James C. McPartland, Charles A. Nelson, Kevin A. Pelphrey, John D. Van Horn, Sara J. Webb, Katy Ankenman, Sarah Corrigan, Dianna Depedro-Mercier, Desiree Guilford, Abha R. Gupta, Zachary Jacokes, Shafali Jeste, Cara M. Keifer, Erin Libsack, Jennifer K. Lowe, Anna Kresse, Erin MacDonnell, Nicole McDonald, Adam Naples, Emily Neuhaus, Catherine A.W. Sullivan, Heidi Tsapelas, Carinna M. Torgerson, Pamela Ventola, Olivia Welker, Julie Wolf

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

Original languageEnglish
Pages (from-to)378-387
Number of pages10
JournalBrain
Volume145
Issue number1
DOIs
StatePublished - 1 Jan 2022
Externally publishedYes

Keywords

  • autism spectrum disorder
  • female protective effect
  • functional connectivity
  • imaging genetics
  • polygenic risk

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