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 Howe; Jacob A. S. Vorstman; Neal Sondheimer; Nicole Takahashi; Judith H. Miles; Evdokia A. Anagnostou; Kristiina Tammimies; Mehdi Zarrei; Daniele Merico; Dimitri James Stavropoulos; Ryan K. C. Yuen; Bridget A. Fernandez; Stephen W. Scherer

doi:10.1038/s41467-022-34112-z

Genetic & Genomic MedicineNature CommunicationsOct 29, 2022

Peer-reviewed journal article

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

Ada J. S. Chan, Worrawat Engchuan iD, Miriam S. Reuter iD, Zhuozhi Wang iD, Bhooma Thiruvahindrapuram iD, Brett Trost iD, Thomas Nalpathamkalam iD, Carol Negrijn, Sylvia Lamoureux, Giovanna Pellecchia iD, Rohan V. Patel iD, Wilson W. L. Sung iD, Jeffrey R. MacDonald iD, Jennifer Howe, Jacob A. S. Vorstman iD, Neal Sondheimer iD, Nicole Takahashi iD, Judith H. Miles iD, Evdokia A. Anagnostou iD, Kristiina Tammimies iD, Mehdi Zarrei, Daniele Merico iD, Dimitri James Stavropoulos iD, Ryan K. C. Yuen iD, Bridget A. Fernandez iD, Stephen W. Scherer iD

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 categorized 325 Canadian children with ASD into dysmorphic and nondysmorphic subgroups. We developed 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 had a significantly higher GRVS compared to those with nondysmorphic ASD (P= 0.027). Using the polygenic transmission disequilibrium test, we observed an over-transmission of ASD-associated common variants in nondysmorphic ASD probands (P= 2.9x10-3). These findings replicated 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.

PDF DOI