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The world’s largest autism study uncovers 134 new genes linked to the condition

The world’s largest autism study uncovers 134 new genes linked to the condition

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Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that affects how a person communicates and interacts with others, as well as how they perceive and respond to the world around them. Symptoms of ASD can range from mild to severe and can include difficulty with social interactions, difficulty with verbal and nonverbal communication, repetitive behavior, and other unique challenges.

A study led by SickKids has sequenced the entire genomes of over 11,000 people, providing new insight into the genetic factors associated with autism spectrum disorders.

Researchers at the Hospital for Sick Children (SickKids) have uncovered new genes and genetic alterations associated with autism spectrum disorders (ASD) in the most comprehensive whole-genome sequencing analysis of autism to date, improving our understanding of the genomic basis of ASD.

The study, published in Cell, used whole genome sequencing to analyze the entire genomes of over 7,000 people with autism and an additional 13,000 siblings and family members. The study found 134 genes associated with ASD and identified a number of genetic alterations, particularly gene copy number variations, that are likely to be associated with autism, including ASD-associated rare variants that are present in approximately 14% of participants with autism are present.

The bulk of the data comes from the Autism Speaks MSSNG database, the world’s largest dataset covering the entire autism genome, giving autism researchers free and open access to thousands of sequenced genes.

“By sequencing the entire genome of all participants and closely involving participating families in MSSNG in setting our research priorities, we maximize discovery potential and enable analysis that encompasses all types of variants, from the smallest DNA changes to entire ones affect chromosomes,” says Dr. Stephen Scherer, Senior Scientist, Genetics & Genome Biology and Chief of Research at SickKids and Director of the McLaughlin Center at the University of Toronto.

dr Brett Trost, lead author of the article and a research associate in the Genetics & Genome Biology program at SickKids, notes that using WGS allowed researchers to uncover variant types that would otherwise have been undetectable. These variant types include complex DNA rearrangements as well as tandem repeat expansions, a finding supported by recent SickKids research on the link between autism and DNA segments that are repeated many times. The role of maternally inherited mitochondrial DNA was also examined in the study and found to account for two percent of autism.

The paper also points to important nuances in autism genetics in families with just one person with autism compared to families with multiple people with autism, known as multiplex families. What surprised the team was that the “polygenic score” – an estimate of the likelihood that a person has autism calculated by aggregating the effects of thousands of common variants across the genome – was no higher in multiplex families.

“This suggests that autism in multiplex families is more likely to be associated with rare, highly potent variants inherited from one parent. Because both the genetics and clinical features associated with autism are so complex and diverse, large datasets like the ones we use are crucial to provide researchers with a clearer understanding of the genetic architecture of autism,” says Trost.

The research team says the study data can help expand investigations into the range of variants that might be associated with ASD, as well as efforts to better understand contributors to the 85 percent of autistic individuals whose genetic cause remains unresolved to understand. In a linked study of 325 Newfoundland families with ASD published in Nature Communications, Dr. Scherer found that combinations of spontaneous, rarely inherited, and polygenic genetic factors concurring in the same person can potentially lead to different subtypes of autism.

dr Suzanne Lewis, a geneticist and researcher at BC Children’s Hospital Research Institute who diagnosed many of the families participating in the study, said: “Taken together, these latest findings represent a tremendous step forward in understanding the complex genetic and biological circuits involved are to better understand ASD. This rich dataset also provides an opportunity to delve deeper into the study of other factors that may determine a person’s likelihood of developing this complex condition, to help individualize future treatment approaches.”

References: “Genomic Architecture of Autism from Comprehensive Annotation of Whole Genome Sequences” by Brett Trost, Bhooma Thiruvahindrapuram, Ada JS 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 WL 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 LY Fong, Sanjeev Pullenayegum, Kozue Samler, Ting Wang, Karen Ho, Tara Paton, Sergio L. Pereira, Jo-Anne Herbrick, Richard F. Wintle, Jonathan Furth, Juti Noppornpitak, Heather Ward, Patrick M age e, 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 AS Vorstman, Khalid A Fakhro, Bridget A Fernandez, ME Suzanne Lewis, Rosanna Weksberg , Marc Fiume, Ryan KC Yuen, Evdokia Anagnostou, Neal Sondheimer, David Glazer, Dean M. Hartley, and Stephen W. Scherer, November 10, 2022, Cell.
DOI: 10.1016/j.cell.2022.10.009

“Genome-wide Rare Variant Score Associates with morphological Subtypes of Autism Spectrum Disorder” by Ada JS Chan, Worrawat Engchuan, Miriam S. Reuter, Zhuozhi Wang, Bhooma Thiruvahindrapuram, Brett Trost, Thomas Nalpathamkalam, Carol Negrijn, Sylvia Lamoureux, Giovanna Pellecchia, Rohan V Patel, Wilson WL 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 KC Yuen, Bridget A Fernandez, and Stephen W Scherer, October 29, 2022, Nature Communications.
DOI: 10.1038/s41467-022-34112-z

Funding was provided by the University of Toronto McLaughlin Centre, Genome Canada/Ontario Genomics, Genome BC, Government of Ontario, Canadian Institutes of Health Research, Canada Foundation for Innovation, Autism Speaks, Autism Speaks Canada, Brain Child, Kids Brain Health Network, Qatar National Research Fund, Ontario Brain Institute, SFARI and SickKids Foundation.

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