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Effect Sizes of Deletions and Duplications on Autism Risk Across the Genome
- Source :
- American Journal of Psychiatry, American Journal of Psychiatry, American Psychiatric Publishing, 2021, 178 (1), pp.87-98. ⟨10.1176/appi.ajp.2020.19080834⟩, The American Journal of Psychiatry, The American Journal of Psychiatry, 2021, 178 (1), pp.87-98. ⟨10.1176/appi.ajp.2020.19080834⟩, Am J Psychiatry
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
Abstract
- International audience; 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.
- Subjects :
- Male
endocrine system diseases
Autism Spectrum Disorder
Intelligence
Genome
Copy Number Variants
0302 clinical medicine
Risk Factors
MESH: Risk Factors
Gene Duplication
MESH: Child
Copy-number variation
Child
Genetics
MESH: Gene Duplication
MESH: Genetic Predisposition to Disease
MESH: Case-Control Studies
Psychiatry and Mental health
Autism spectrum disorder
Female
MESH: DNA Copy Number Variations
Adult
congenital, hereditary, and neonatal diseases and abnormalities
Adolescent
DNA Copy Number Variations
MESH: Autistic Disorder
Biology
behavioral disciplines and activities
Article
03 medical and health sciences
mental disorders
medicine
Humans
Genetic Predisposition to Disease
MESH: Genome
MESH: Intelligence
Autistic Disorder
MESH: Adolescent
MESH: Humans
[SCCO.NEUR]Cognitive science/Neuroscience
MESH: Adult
medicine.disease
MESH: Male
030227 psychiatry
IQ
MESH: Gene Deletion
Case-Control Studies
Autism
MESH: Female
Gene Deletion
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 0002953X and 15357228
- Database :
- OpenAIRE
- Journal :
- American Journal of Psychiatry, American Journal of Psychiatry, American Psychiatric Publishing, 2021, 178 (1), pp.87-98. ⟨10.1176/appi.ajp.2020.19080834⟩, The American Journal of Psychiatry, The American Journal of Psychiatry, 2021, 178 (1), pp.87-98. ⟨10.1176/appi.ajp.2020.19080834⟩, Am J Psychiatry
- Accession number :
- edsair.doi.dedup.....db6d4157b56e6bd11cc7159f126268ec