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

Ada J. S. Chan, Worrawat Engchuan, Miriam S. Reuter, Zhuozhi Wang, Bhooma Thiruvahindrapuram, Brett Trost, Thomas Nalpathamkalam, Carol Negrijn, Sylvia Lamoureux, Giovanna Pellecchia, Rohan V. Patel, Wilson W. L. Sung, Jeffrey R. MacDonald, Jennifer L. Howe, Jacob Vorstman, Neal Sondheimer, Nicole Takahashi, Judith H. Miles, Evdokia Anagnostou, Kristiina Tammimies, Mehdi Zarrei, Daniele Merico, Dimitri J. Stavropoulos, Ryan K. C. Yuen, Bridget A. Fernandez () and Stephen W. Scherer ()
Additional contact information
Ada J. S. Chan: The Hospital for Sick Children
Worrawat Engchuan: The Hospital for Sick Children
Miriam S. Reuter: The Hospital for Sick Children
Zhuozhi Wang: The Hospital for Sick Children
Bhooma Thiruvahindrapuram: The Hospital for Sick Children
Brett Trost: The Hospital for Sick Children
Thomas Nalpathamkalam: The Hospital for Sick Children
Carol Negrijn: Eastern Health
Sylvia Lamoureux: The Hospital for Sick Children
Giovanna Pellecchia: The Hospital for Sick Children
Rohan V. Patel: The Hospital for Sick Children
Wilson W. L. Sung: The Hospital for Sick Children
Jeffrey R. MacDonald: The Hospital for Sick Children
Jennifer L. Howe: The Hospital for Sick Children
Jacob Vorstman: The Hospital for Sick Children
Neal Sondheimer: University of Toronto
Nicole Takahashi: University of Missouri
Judith H. Miles: University of Missouri
Evdokia Anagnostou: University of Toronto
Kristiina Tammimies: Karolinska Institutet
Mehdi Zarrei: The Hospital for Sick Children
Daniele Merico: The Hospital for Sick Children
Dimitri J. Stavropoulos: The Hospital for Sick Children
Ryan K. C. Yuen: The Hospital for Sick Children
Bridget A. Fernandez: Eastern Health
Stephen W. Scherer: The Hospital for Sick Children

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34112-z

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