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; Stephen W Scherer

doi:10.1038/s41467-022-34112-z

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

Nat Commun. 2022 Oct 29;13(1):6463. doi: 10.1038/s41467-022-34112-z.

Authors

Ada J S Chan^{1

2}, Worrawat Engchuan^{1

2}, Miriam S Reuter^{1

2

3}, Zhuozhi Wang^{1

2}, Bhooma Thiruvahindrapuram^{1

2}, Brett Trost^{1

2}, Thomas Nalpathamkalam^{1

2}, Carol Negrijn⁴, Sylvia Lamoureux^{1

2}, Giovanna Pellecchia^{1

2}, Rohan V Patel^{1

2}, Wilson W L Sung^{1

2}, Jeffrey R MacDonald^{1

2}, Jennifer L Howe^{1

2}, Jacob Vorstman^{1

5

6}, Neal Sondheimer^{7

8

9}, Nicole Takahashi¹⁰, Judith H Miles¹⁰, Evdokia Anagnostou^{9

11}, Kristiina Tammimies¹², Mehdi Zarrei^{1

2}, Daniele Merico^{1

13}, Dimitri J Stavropoulos^{14

15}, Ryan K C Yuen^{1

2

7}, Bridget A Fernandez^{16

17

18}, Stephen W Scherer^{19

20

21

22}

Affiliations

¹ The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
² Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
³ CGEn, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Provincial Medical Genetics Program, Eastern Health, St. John's, NL, Canada.
⁵ Department of Psychiatry, The Hospital for Sick Children, Toronto, ON, Canada.
⁶ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁷ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁸ Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
⁹ Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
¹⁰ Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri, Columbia, MO, USA.
¹¹ Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada.
¹² Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
¹³ Deep Genomics Inc., Toronto, ON, Canada.
¹⁴ Department of Paediatric Laboratory Medicine, Genome Diagnostics, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁵ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁶ Provincial Medical Genetics Program, Eastern Health, St. John's, NL, Canada. bfernandez@chla.usc.edu.
¹⁷ Department of Pediatrics and The Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA. bfernandez@chla.usc.edu.
¹⁸ Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada. bfernandez@chla.usc.edu.
¹⁹ The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada. stephen.scherer@sickkids.ca.
²⁰ Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada. stephen.scherer@sickkids.ca.
²¹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. stephen.scherer@sickkids.ca.
²² McLaughlin Centre, University of Toronto, Toronto, ON, Canada. stephen.scherer@sickkids.ca.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autism Spectrum Disorder* / genetics
Canada / epidemiology
Child
Genetic Predisposition to Disease
Genome
Humans
Multifactorial Inheritance / genetics
Whole Genome Sequencing