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Updated: Dec 9, 2025
A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia
Published on: June 15, 2011
Effect Sizes of Deletions and Duplications on Autism Risk Across the Genome
Elise Douard1, Abderrahim Zeribi1, Catherine Schramm1
1Université de Montréal, Montreal (Douard, Zeribi, Schramm, Tamer, Loum, Nowak, Lord, Moreau, Huguet, Jacquemont); UHC Sainte-Justine Research Center, Montreal (Douard, Zeribi, Schramm, Tamer, Loum, Nowak, Saci, Lord, Rodríguez-Herreros, Jean-Louis, Moreau, Huguet, Jacquemont); Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal (Schramm, Greenwood); Sensory-Motor Laboratory, Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland (Rodríguez-Herreros); Department of Forensic and Neurodevelopmental Sciences (Loth) and Center for Population Neuroscience and Stratified Medicine (Schumann), Institute of Psychiatry, Psychology, and Neuroscience, King's College London; Hospital for Sick Children and Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto (Pausova); Departments of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal (Elsabbagh); Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, and Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia (Almasy); Department of Psychiatry, Boston Children's Hospital and Harvard Medical School, Boston (Glahn); Human Genetics and Cognitive Functions, Institut Pasteur, Université de Paris, Paris (Bourgeron); Département de Sciences de la Décision, HEC Montreal, Montreal (Labbe); Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto (Paus); Departments of Psychology and Psychiatry, University of Toronto, Toronto (Paus); Centre de Recherche de CIUSSS-NIM, Montreal (Mottron); Département de Psychiatrie, Université de Montréal, Montreal (Mottron); Department of Epidemiology, Biostatistics, and Occupational Health, Gerald Bronfman Department of Oncology, and Department of Human Genetics, McGill University, Montreal (Greenwood).
Objective:
Deleterious copy number variants (CNVs) are identified in up to 20% of individuals with autism. However, levels of autism risk conferred by most rare CNVs remain unknown. The authors recently developed statistical models to estimate the effect size on IQ of all CNVs, including undocumented ones. In this study, the authors extended this model to autism susceptibility.
Methods:
The authors identified CNVs in two autism populations (Simons Simplex Collection and MSSNG) and two unselected populations (IMAGEN and Saguenay Youth Study). Statistical models were used to test nine quantitative variables associated with genes encompassed in CNVs to explain their effects on IQ, autism susceptibility, and behavioral domains.
Results:
The "probability of being loss-of-function intolerant" (pLI) best explains the effect of CNVs on IQ and autism risk. Deleting 1 point of pLI decreases IQ by 2.6 points in autism and unselected populations. The effect of duplications on IQ is threefold smaller. Autism susceptibility increases when deleting or duplicating any point of pLI. This is true for individuals with high or low IQ and after removing de novo and known recurrent neuropsychiatric CNVs. When CNV effects on IQ are accounted for, autism susceptibility remains mostly unchanged for duplications but decreases for deletions. Model estimates for autism risk overlap with previously published observations. Deletions and duplications differentially affect social communication, behavior, and phonological memory, whereas both equally affect motor skills.
Conclusions:
Autism risk conferred by duplications is less influenced by IQ compared with deletions. The model applied in this study, trained on CNVs encompassing >4,500 genes, suggests highly polygenic properties of gene dosage with respect to autism risk and IQ loss. These models will help to interpret CNVs identified in the clinic.
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