Effect sizes of deletions and duplications on autism risk across the genome

Elise Douard, Abderrahim Zeribi, Catherine Schramm, Petra Tamer, Mor Absa Loum, Sabrina Nowak, Zohra Saci, Marie Pier Lord, Borja Rodríguez-Herreros, Martineau Jean-Louis, Clara Moreau, Eva Loth, Gunter Schumann, Zdenka Pausova, Mayada Elsabbagh, Laura Almasy, David C. Glahn, Thomas Bourgeron, Aurélie Labbe, Tomas PausLaurent Mottron, Celia M.T. Greenwood, Guillaume Huguet, Sébastien Jacquemont

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)87-98
Number of pages12
JournalAmerican Journal of Psychiatry
Volume178
Issue number1
DOIs
StatePublished - Jan 2021
Externally publishedYes

ASJC Scopus subject areas

  • Psychiatry and Mental health

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