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

Katherine E Lawrence¹, Leanna M Hernandez¹, Emily Fuster¹, Namita T Padgaonkar¹, Genevieve Patterson¹, Jiwon Jung¹, Nana J Okada¹, Jennifer K Lowe², Jackson N Hoekstra², Allison Jack³, Elizabeth Aylward⁴, Nadine Gaab⁵, John D Van Horn⁶, Raphael A Bernier⁷, James C McPartland⁸, Sara J Webb^{7

9}, Kevin A Pelphrey¹⁰, Shulamite A Green¹, Susan Y Bookheimer¹, Daniel H Geschwind^{2

11}, Mirella Dapretto¹; GENDAAR Consortium

Collaborators, Affiliations

Affiliations

¹ Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA 90095, USA.
² Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Psychology, George Mason University, Fairfax, VA 22030, USA.
⁴ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
⁵ Harvard Graduate School of Education, Cambridge, MA 02138, USA.
⁶ Department of Psychology and School of Data Science, University of Virginia, Charlottesville, VA 22904, USA.
⁷ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
⁸ Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA.
⁹ Center on Child Health, Behavior, and Development, Seattle Children's Research Institute, Seattle, WA 98101, USA.
¹⁰ Department of Neurology, University of Virginia, Charlottesville, VA 22904, USA.
¹¹ Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA, 90095, USA.

PMID: 34050743
PMCID: PMC8967090
DOI: 10.1093/brain/awab204

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

Katherine E Lawrence et al. Brain. 2022.

. 2022 Mar 29;145(1):378-387.

doi: 10.1093/brain/awab204.

Authors

Affiliations

¹ Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA 90095, USA.
² Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Psychology, George Mason University, Fairfax, VA 22030, USA.
⁴ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
⁵ Harvard Graduate School of Education, Cambridge, MA 02138, USA.
⁶ Department of Psychology and School of Data Science, University of Virginia, Charlottesville, VA 22904, USA.
⁷ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
⁸ Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA.
⁹ Center on Child Health, Behavior, and Development, Seattle Children's Research Institute, Seattle, WA 98101, USA.
¹⁰ Department of Neurology, University of Virginia, Charlottesville, VA 22904, USA.
¹¹ Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA, 90095, USA.

PMID: 34050743
PMCID: PMC8967090
DOI: 10.1093/brain/awab204

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.

Keywords: autism spectrum disorder; female protective effect; functional connectivity; imaging genetics; polygenic risk.

PubMed Disclaimer

Figures

**Figure 1**
**Effects of polygenic risk for ASD on salience network functional connectivity among youth with ASD.** (A) In boys with ASD, greater polygenic risk was associated with increased functional connectivity between the salience network and the postcentral and supramarginal gyri. (B) When comparing boys and girls with ASD, distinct effects of polygenic risk were observed on salience network functional connectivity with the precentral gyrus and mid-insula. Graphs are for illustrative purposes only and represent the relationship between untransformed PRSs and mean connectivity z-scores extracted from each significant cluster at the *left*. L = left.

**Figure 2**
**Effects of polygenic risk for ASD on salience network functional connectivity among TD youth**. (A) In TD boys, greater polygenic risk was associated with increased functional connectivity between the salience network and the precentral and postcentral gyri. (B) In TD boys, increasing polygenic risk was related to weaker salience network functional connectivity with the inferior temporal gyrus. (C) When comparing TD boys and girls, distinct effects of polygenic risk were observed on salience network functional connectivity with the precentral gyrus. Graphs are for illustrative purposes only and represent the relationship between untransformed polygenic risk scores and mean connectivity z-scores extracted from each significant cluster at left. L = left.

See this image and copyright information in PMC

References

1. Tick B, Bolton P, Happe F, Rutter M, Rijsdijk F.. Heritability of autism spectrum disorders: A meta-analysis of twin studies. J Child Psychol Psychiatry. 2016;57(5):585–595. - PMC - PubMed
1. Anney R, Klei L, Pinto D, et al.Individual common variants exert weak effects on the risk for autism spectrum disorders. Hum Mol Genet. 2012;21(21):4781–4792. - PMC - PubMed
1. Gaugler T, Klei L, Sanders SJ, et al.Most genetic risk for autism resides with common variation. Nat Genet. 2014;46(8):881–885. - PMC - PubMed
1. Klei L, Sanders SJ, Murtha MT, et al.Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism. 2012;3(1):9. - PMC - PubMed
1. de la Torre-Ubieta L, Won H, Stein JL, Geschwind DH.. Advancing the understanding of autism disease mechanisms through genetics. Nat Med. 2016;22(4):345–361. - PMC - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Medical
- MedlinePlus Consumer Health Information
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical