%0 Journal Article %T Measuring and Estimating the Effect Sizes of Copy Number Variants on General Intelligence in Community-Based Samples %+ Université de Montréal (UdeM) %+ CHU Sainte Justine [Montréal] %+ Lady Davis Institute for Medical Research [Montréal] %+ HEC Montréal (HEC Montréal) %+ Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)) %+ Gènes, Synapses et Cognition (CNRS - UMR3571 ) %+ Lawrence Berkeley National Laboratory [Berkeley] (LBNL) %+ Institute of Psychiatry, Psychology & Neuroscience, King's College London %+ University of Toronto %+ McGill University = Université McGill [Montréal, Canada] %+ Rotman Research Institute at the Baycrest Centre (RRI) %+ Child Mind Institute %A Huguet, Guillaume %A Schramm, Catherine %A Douard, Elise %A Jiang, Lai %A Labbe, Aurélie %A Tihy, Frédérique %A Mathonnet, Géraldine %A Nizard, Sonia %A Lemyre, Emmanuelle %A Alexandre, Mathieu %A Poline, Jean-Baptiste %A Loth, Eva %A Toro, Roberto %A Schumann, Gunter %A Conrod, Patricia %A Pausova, Zdenka %A Greenwood, Celia %A Paus, Tomas %A Bourgeron, Thomas %A Jacquemont, Sébastien %Z This research was enabled by support provided by Calcul Quebec (http://www.calculquebec.ca) and Compute Canada (http://www.computecanada.ca). Dr Bourgeron is supported by the Institut Pasteur, the University Paris Diderot, Centre National de la Recherche Scientifique, and the Bettencourt-Schueller Foundation. Dr Jacquemont is a recipient of a Bursary Professor fellowship of the Swiss National Science Foundation, a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. Dr Huguet is supported by the Sainte-Justine Foundation, the Merit scholarship program for foreign students, and the Network of Applied Genetic Medicine fellowships. Dr Schramm is supported by the Institute for Data Valorization fellowship. Dr Loth is supported by European Autism Interventions, which receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement 115300, the resources of which are composed of financial contributions from grant FP7/2007-2013 from the European Union's Seventh Framework Programme, the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions, and Autism Speaks. This work is supported by a grant from the Brain Canada Multi Investigator initiative (Dr Jacquemont). The Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada fund the Saguenay Youth Study. Funding for the project was provided by the Wellcome Trust. %< avec comité de lecture %@ 2168-622X %J JAMA Psychiatry %I Chicago, IL : American Medical Association, [2013]- %V 75 %N 5 %P 447-457 %8 2018-05-01 %D 2018 %R 10.1001/jamapsychiatry.2018.0039 %M 29562078 %Z Life Sciences [q-bio]Journal articles %X IMPORTANCE:Copy number variants (CNVs) classified as pathogenic are identified in 10% to 15% of patients referred for neurodevelopmental disorders. However, their effect sizes on cognitive traits measured as a continuum remain mostly unknown because most of them are too rare to be studied individually using association studies.OBJECTIVE:To measure and estimate the effect sizes of recurrent and nonrecurrent CNVs on IQ.DESIGN, SETTING, AND PARTICIPANTS:This study identified all CNVs that were 50 kilobases (kb) or larger in 2 general population cohorts (the IMAGEN project and the Saguenay Youth Study) with measures of IQ. Linear regressions, including functional annotations of genes included in CNVs, were used to identify features to explain their association with IQ. Validation was performed using intraclass correlation that compared IQ estimated by the model with empirical data.MAIN OUTCOMES AND MEASURES:Performance IQ (PIQ), verbal IQ (VIQ), and frequency of de novo CNV events.RESULTS:The study included 2090 European adolescents from the IMAGEN study and 1983 children and parents from the Saguenay Youth Study. Of these, genotyping was performed on 1804 individuals from IMAGEN and 977 adolescents, 445 mothers, and 448 fathers (484 families) from the Saguenay Youth Study. We observed 4928 autosomal CNVs larger than 50 kb across both cohorts. For rare deletions, size, number of genes, and exons affect IQ, and each deleted gene is associated with a mean (SE) decrease in PIQ of 0.67 (0.19) points (P = 6 × 10-4); this is not so for rare duplications and frequent CNVs. Among 10 functional annotations, haploinsufficiency scores best explain the association of any deletions with PIQ with a mean (SE) decrease of 2.74 (0.68) points per unit of the probability of being loss-of-function intolerant (P = 8 × 10-5). Results are consistent across cohorts and unaffected by sensitivity analyses removing pathogenic CNVs. There is a 0.75 concordance (95% CI, 0.39-0.91) between the effect size on IQ estimated by our model and IQ loss calculated in previous studies of 15 recurrent CNVs. There is a close association between effect size on IQ and the frequency at which deletions occur de novo (odds ratio, 0.86; 95% CI, 0.84-0.87; P = 2.7 × 10-88). There is a 0.76 concordance (95% CI, 0.41-0.91) between de novo frequency estimated by the model and calculated using data from the DECIPHER database.CONCLUSIONS AND RELEVANCE:Models trained on nonpathogenic deletions in the general population reliably estimate the effect size of pathogenic deletions and suggest omnigenic associations of haploinsufficiency with IQ. This represents a new framework to study variants too rare to perform individual association studies and can help estimate the cognitive effect of undocumented deletions in the neurodevelopmental clinic. %G English %L pasteur-01967227 %U https://pasteur.hal.science/pasteur-01967227 %~ PASTEUR %~ UNIV-PARIS7 %~ CNRS %~ OPENAIRE %~ USPC %~ UNIV-PARIS %~ UP-SCIENCES %~ TEST-HALCNRS %~ HUM-GEN-COGN-FUN %~ PASTEUR_UMR3571