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A genome-first study of sex chromosome aneuploidies provides evidence of Y chromosome dosage effects on autism risk

Author

Listed:
  • Alexander S. F. Berry

    (Geisinger)

  • Brenda M. Finucane

    (Geisinger)

  • Scott M. Myers

    (Geisinger)

  • Lauren K. Walsh

    (Geisinger)

  • John M. Seibert

    (Geisinger)

  • Christa Lese Martin

    (Geisinger)

  • David H. Ledbetter

    (University of Florida College of Medicine)

  • Matthew T. Oetjens

    (Geisinger)

Abstract

A female protective effect has long been postulated as the primary explanation for the four-fold increase of autism spectrum disorder (ASD) diagnoses in males versus females. However, genetic and epidemiological investigations of this hypothesis have so far failed to explain the large difference in ASD prevalence between the sexes. To address this knowledge gap, we examined sex chromosome aneuploidy in a large ASD case-control cohort to evaluate the relationship between X and Y chromosome dosage and ASD risk. From these data, we modeled three relationships between sex chromosome dosage and ASD risk: the extra Y effect, the extra X effect, and sex chromosome haploinsufficiency. We found that the extra Y effect increased ASD risk significantly more than the extra X effect. Among females, we observed a large association between 45, X and ASD, confirming sex chromosome haploinsufficiency as a strong ASD risk factor. These results provide a framework for understanding the relationship between X and Y chromosome dosage on ASD, which may inform future research investigating genomic contributors to the observed sex difference.

Suggested Citation

  • Alexander S. F. Berry & Brenda M. Finucane & Scott M. Myers & Lauren K. Walsh & John M. Seibert & Christa Lese Martin & David H. Ledbetter & Matthew T. Oetjens, 2024. "A genome-first study of sex chromosome aneuploidies provides evidence of Y chromosome dosage effects on autism risk," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53211-7
    DOI: 10.1038/s41467-024-53211-7
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    References listed on IDEAS

    as
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    3. Helen Skaletsky & Tomoko Kuroda-Kawaguchi & Patrick J. Minx & Holland S. Cordum & LaDeana Hillier & Laura G. Brown & Sjoerd Repping & Tatyana Pyntikova & Johar Ali & Tamberlyn Bieri & Asif Chinwalla &, 2003. "The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes," Nature, Nature, vol. 423(6942), pages 825-837, June.
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