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Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder

Author

Listed:
  • Ada J. S. Chan

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Worrawat Engchuan

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Miriam S. Reuter

    (The Hospital for Sick Children
    The Hospital for Sick Children
    The Hospital for Sick Children)

  • Zhuozhi Wang

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Bhooma Thiruvahindrapuram

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Brett Trost

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Thomas Nalpathamkalam

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Carol Negrijn

    (Eastern Health)

  • Sylvia Lamoureux

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Giovanna Pellecchia

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Rohan V. Patel

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Wilson W. L. Sung

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Jeffrey R. MacDonald

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Jennifer L. Howe

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Jacob Vorstman

    (The Hospital for Sick Children
    The Hospital for Sick Children
    University of Toronto)

  • Neal Sondheimer

    (University of Toronto
    The Hospital for Sick Children
    University of Toronto)

  • Nicole Takahashi

    (University of Missouri)

  • Judith H. Miles

    (University of Missouri)

  • Evdokia Anagnostou

    (University of Toronto
    Holland Bloorview Kids Rehabilitation Hospital)

  • Kristiina Tammimies

    (Karolinska Institutet)

  • Mehdi Zarrei

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Daniele Merico

    (The Hospital for Sick Children
    Deep Genomics Inc.)

  • Dimitri J. Stavropoulos

    (The Hospital for Sick Children
    University of Toronto)

  • Ryan K. C. Yuen

    (The Hospital for Sick Children
    The Hospital for Sick Children
    University of Toronto)

  • Bridget A. Fernandez

    (Eastern Health
    Children’s Hospital Los Angeles, Keck School of Medicine of University of Southern California
    Memorial University of Newfoundland)

  • Stephen W. Scherer

    (The Hospital for Sick Children
    The Hospital for Sick Children
    University of Toronto
    University of Toronto)

Abstract

Defining different genetic subtypes of autism spectrum disorder (ASD) can enable the prediction of developmental outcomes. Based on minor physical and major congenital anomalies, we categorize 325 Canadian children with ASD into dysmorphic and nondysmorphic subgroups. We develop a method for calculating a patient-level, genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data. GRVS is a sum of the number of variants in morphology-associated coding and non-coding regions, weighted by their effect sizes. Probands with dysmorphic ASD have a significantly higher GRVS compared to those with nondysmorphic ASD (P = 0.03). Using the polygenic transmission disequilibrium test, we observe an over-transmission of ASD-associated common variants in nondysmorphic ASD probands (P = 2.9 × 10−3). These findings replicate using WGS data from 442 ASD probands with accompanying morphology data from the Simons Simplex Collection. Our results provide support for an alternative genomic classification of ASD subgroups using morphology data, which may inform intervention protocols.

Suggested Citation

  • Ada J. S. Chan & Worrawat Engchuan & Miriam S. Reuter & Zhuozhi Wang & Bhooma Thiruvahindrapuram & Brett Trost & Thomas Nalpathamkalam & Carol Negrijn & Sylvia Lamoureux & Giovanna Pellecchia & Rohan , 2022. "Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34112-z
    DOI: 10.1038/s41467-022-34112-z
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