Genomic architecture of autism from comprehensive whole-genome sequence annotation

Brett Trost; Bhooma Thiruvahindrapuram; Ada J S Chan; Worrawat Engchuan; Edward J Higginbotham; Jennifer L Howe; Livia O Loureiro; Miriam S Reuter; Delnaz Roshandel; Joe Whitney; Mehdi Zarrei; Matthew Bookman; Cherith Somerville; Rulan Shaath; Mona Abdi; Elbay Aliyev; Rohan V Patel; Thomas Nalpathamkalam; Giovanna Pellecchia; Omar Hamdan; Gaganjot Kaur; Zhuozhi Wang; Jeffrey R MacDonald; John Wei; Wilson W L Sung; Sylvia Lamoureux; Ny Hoang; Thanuja Selvanayagam; Nicole Deflaux; Melissa Geng; Siavash Ghaffari; John Bates; Edwin J Young; Qiliang Ding; Carole Shum; Lia D'Abate; Clarrisa A Bradley; Annabel Rutherford; Vernie Aguda; Beverly Apresto; Nan Chen; Sachin Desai; Xiaoyan Du; Matthew L Y Fong; Sanjeev Pullenayegum; Kozue Samler; Ting Wang; Karen Ho; Tara Paton; Sergio L Pereira; Jo-Anne Herbrick; Richard F Wintle; Jonathan Fuerth; Juti Noppornpitak; Heather Ward; Patrick Magee; Ayman Al Baz; Usanthan Kajendirarajah; Sharvari Kapadia; Jim Vlasblom; Monica Valluri; Joseph Green; Vicki Seifer; Morgan Quirbach; Olivia Rennie; Elizabeth Kelley; Nina Masjedi; Catherine Lord; Michael J Szego; Ma'n H Zawati; Michael Lang; Lisa J Strug; Christian R Marshall; Gregory Costain; Kristina Calli; Alana Iaboni; Afiqah Yusuf; Patricia Ambrozewicz; Louise Gallagher; David G Amaral; Jessica Brian; Mayada Elsabbagh; Stelios Georgiades; Daniel S Messinger; Sally Ozonoff; Jonathan Sebat; Calvin Sjaarda; Isabel M Smith; Peter Szatmari; Lonnie Zwaigenbaum; Azadeh Kushki; Thomas W Frazier; Jacob A S Vorstman; Khalid A Fakhro; Bridget A Fernandez; M E Suzanne Lewis; Rosanna Weksberg; Marc Fiume; Ryan K C Yuen; Evdokia Anagnostou; Neal Sondheimer; David Glazer; Dean M Hartley; Stephen W Scherer

doi:10.1016/j.cell.2022.10.009

Genomic architecture of autism from comprehensive whole-genome sequence annotation

Cell. 2022 Nov 10;185(23):4409-4427.e18. doi: 10.1016/j.cell.2022.10.009.

Authors

Brett Trost¹, Bhooma Thiruvahindrapuram², Ada J S Chan¹, Worrawat Engchuan¹, Edward J Higginbotham¹, Jennifer L Howe², Livia O Loureiro¹, Miriam S Reuter³, Delnaz Roshandel⁴, Joe Whitney², Mehdi Zarrei¹, Matthew Bookman⁵, Cherith Somerville⁶, Rulan Shaath², Mona Abdi⁷, Elbay Aliyev⁸, Rohan V Patel², Thomas Nalpathamkalam², Giovanna Pellecchia², Omar Hamdan², Gaganjot Kaur², Zhuozhi Wang², Jeffrey R MacDonald², John Wei², Wilson W L Sung², Sylvia Lamoureux², Ny Hoang⁹, Thanuja Selvanayagam¹⁰, Nicole Deflaux⁵, Melissa Geng¹¹, Siavash Ghaffari¹, John Bates⁵, Edwin J Young¹², Qiliang Ding⁶, Carole Shum¹, Lia D'Abate¹, Clarrisa A Bradley¹³, Annabel Rutherford¹⁴, Vernie Aguda², Beverly Apresto², Nan Chen², Sachin Desai², Xiaoyan Du², Matthew L Y Fong², Sanjeev Pullenayegum², Kozue Samler², Ting Wang², Karen Ho², Tara Paton², Sergio L Pereira², Jo-Anne Herbrick², Richard F Wintle², Jonathan Fuerth¹⁵, Juti Noppornpitak¹⁵, Heather Ward¹⁵, Patrick Magee¹⁵, Ayman Al Baz¹⁵, Usanthan Kajendirarajah¹⁵, Sharvari Kapadia¹⁵, Jim Vlasblom¹⁵, Monica Valluri¹⁵, Joseph Green¹⁵, Vicki Seifer¹⁶, Morgan Quirbach¹⁶, Olivia Rennie², Elizabeth Kelley¹⁷, Nina Masjedi¹⁸, Catherine Lord¹⁸, Michael J Szego¹⁹, Ma'n H Zawati²⁰, Michael Lang²⁰, Lisa J Strug²¹, Christian R Marshall²², Gregory Costain²³, Kristina Calli²⁴, Alana Iaboni²⁵, Afiqah Yusuf²⁶, Patricia Ambrozewicz²⁷, Louise Gallagher²⁸, David G Amaral²⁹, Jessica Brian³⁰, Mayada Elsabbagh²⁶, Stelios Georgiades³¹, Daniel S Messinger³², Sally Ozonoff²⁹, Jonathan Sebat³³, Calvin Sjaarda³⁴, Isabel M Smith³⁵, Peter Szatmari³⁶, Lonnie Zwaigenbaum³⁷, Azadeh Kushki³⁸, Thomas W Frazier³⁹, Jacob A S Vorstman⁴⁰, Khalid A Fakhro⁴¹, Bridget A Fernandez⁴², M E Suzanne Lewis²⁴, Rosanna Weksberg⁴³, Marc Fiume¹⁵, Ryan K C Yuen¹¹, Evdokia Anagnostou³⁰, Neal Sondheimer⁴⁴, David Glazer⁵, Dean M Hartley¹⁶, Stephen W Scherer⁴⁵

Affiliations

¹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
² The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; CGEn, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁴ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
⁵ Verily Life Sciences, South San Francisco, CA 94080, USA.
⁶ Ted Rogers Centre for Heart Research, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁷ Department of Human Genetics, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁸ Department of Human Genetics, Sidra Medicine, Doha, Qatar.
⁹ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Autism Research Unit, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
¹⁰ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Autism Research Unit, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
¹¹ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹² Genome Diagnostics, Department of Paediatric Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
¹³ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
¹⁴ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁵ DNAstack, Toronto, ON M5H 1T1, Canada.
¹⁶ Autism Speaks, Princeton, NJ 08540, USA.
¹⁷ Department of Psychology, Queen's University, Kingston, ON K7L 3N6, Canada; Department of Psychiatry, Queen's University, Kingston, ON K7L 7X3, Canada.
¹⁸ Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA 90024, USA.
¹⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Family and Community Medicine, University of Toronto, Toronto, ON M5G 1V7, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada.
²⁰ Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
²¹ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Statistical Sciences, University of Toronto, Toronto, ON M5S 3G3, Canada.
²² Genome Diagnostics, Department of Paediatric Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
²³ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
²⁴ Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.
²⁵ Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON M4G 1R8, Canada.
²⁶ Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
²⁷ Autism Research Unit, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Psychology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
²⁸ Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin 2, Ireland; Department of Psychiatry, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Child, Youth and Family Services, The Centre for Addiction and Mental Health, Toronto, ON M6J 1H4, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada.
²⁹ MIND Institute, University of California, Davis, Sacramento, CA 95817, USA; Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, CA 95817, USA.
³⁰ Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada; Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON M4G 1R8, Canada.
³¹ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON L8N 3K7, Canada.
³² Department of Psychology, University of Miami, Miami, FL 33124, USA.
³³ Department of Psychiatry and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
³⁴ Department of Psychiatry, Queen's University, Kingston, ON K7L 7X3, Canada; Queen's Genomics Lab at Ongwanada, Queen's University, Kingston, ON K7M 8A6, Canada.
³⁵ Department of Pediatrics, Dalhousie University, Halifax, NS B3H 4R2, Canada; IWK Health Centre, Halifax, NS B3K 6R8, Canada.
³⁶ Department of Psychiatry, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Centre for Addiction and Mental Health, Toronto, ON M6J 1H4, Canada.
³⁷ Department of Pediatrics, University of Alberta, Edmonton, AB T6G 1C9, Canada.
³⁸ Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON M4G 1R8, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
³⁹ Autism Speaks, Princeton, NJ 08540, USA; Department of Psychology, John Carroll University, Cleveland, OH 44118, USA.
⁴⁰ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada.
⁴¹ Department of Human Genetics, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar; Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Doha, Qatar.
⁴² Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USA.
⁴³ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
⁴⁴ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
⁴⁵ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; McLaughlin Centre, Toronto, ON M5G 0A4, Canada. Electronic address: stephen.scherer@sickkids.ca.

Abstract

Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.

Keywords: autism spectrum disorder; copy-number variation; neurodevelopmental disorders; phenotype measures; polygenic risk scores; rare variants; structural variation; whole-genome sequencing.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Autism Spectrum Disorder* / genetics
Autistic Disorder*
DNA Copy Number Variations / genetics
Genetic Predisposition to Disease
Genomics
Humans

Abstract

Publication types

MeSH terms

Grants and funding