Measuring and Estimating the Effect Sizes of Copy Number Variants on General Intelligence in Community-Based Samples

Huguet, Guillaume; Schramm, Catherine; Douard, Élise; Jiang, Lai; Labbe, Aurélie; Tihy, Frédérique; Mathonnet, Géraldine; Nizard, Sonia; Lemyre, Emmanuelle; Mathieu, Alexandre; Poline, Jean‐Baptiste; Loth, Eva; Toro, Roberto; Schumann, Günter; Conrod, Patricia J.; Pausová, Zdenka; Greenwood, Celia; Paus, Tomáš; Bourgeron, Thomas; Jacquemont, Sébastien

doi:10.1001/jamapsychiatry.2018.0039

Cited by 91 publications

(156 citation statements)

References 46 publications

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“…We previously reported that statistical models, trained on benign deletions in populations not selected for a clinical condition, can accurately estimate the effect-size of deleterious deletions on non-verbal IQ (NVIQ). (26) These results suggest that 1) the effect-size of deletions on NVIQ can be estimated using constraint scores, such as the "probability of being Loss-of-function Intolerant" (pLI, definition in textbox, Figure 1) (27), and 2) the effect of haploinsufficiency on NVIQ applies to a large proportion of the genome, consistent with a highly polygenic model. (28,29) Using pLI as an explanatory variable, we estimated that one third of the coding genes affect NVIQ by >1 point, when deleted.…”

Section: Introductionmentioning

confidence: 74%

“…As we previously observed in unselected populations (26), the variable selection procedure identified the sum of pLI scores as the variable that best explains the variance of NVIQ in the SSC for deletions (r 2 =0.013) and duplications (r 2 =0.004), compared to the Table S11 in the online supplement, Figure 2A).…”

Section: Effect-size Of Gene Dosage On General Intelligence In Probanmentioning

confidence: 96%

“…We included 2,769 individuals from two community-based cohorts that we previously studied (26): IMAGEN (N=1,802) (32) and the Saguenay Youth Study (SYS; N=967) (33) ( Figure 1 and Table S1 in the online supplement).…”

Section: Unselected Cohortsmentioning

confidence: 99%

“…We developed a prediction tool available online (https://cnvprediction.urca.ca/) to estimate the effect-size of deletions and duplications on NVIQ, autism risk and the SRS score. As an illustration, our model estimates a decrease in NVIQ of 26 Table S6. Briefly summarized, this tool should be viewed as a translation of gnomAD (43) information into phenotypic effect-sizes.…”

Section: Potential Applications In the Clinicmentioning

confidence: 99%

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Effects-sizes of deletions and duplications on autism risk across the genome

Douard

Zeribi

Schramm

et al. 2020

Preprint

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Objective: Deleterious copy number variants (CNVs) are identified in up to 20% of individuals with autism. However, only 13 genomic loci have been formally associated with autism because the majority of CNVs are too rare to perform individual association studies. To investigate the implication of undocumented CNVs in neurodevelopmental disorders, we recently developed a new framework to estimate their effect-size on intelligence quotient (IQ) and sought to extend this approach to autism susceptibility and multiple cognitive domains. Methods: We identified CNVs in two autism samples (Simons Simplex Collection and MSSNG) and two unselected populations (IMAGEN and Saguenay Youth Study). Statistical models integrating scores of genes encompassed in CNVs were used to explain their effect on autism susceptibility and multiple cognitive domains. Results: Among 9 scores of genes, the "probability-of-being loss-of-function intolerant" (pLI) best explains the effect of CNVs on IQ and autism risk. Deletions decrease IQ by a mean of 2.6 points per point of pLI. The effect of duplications on IQ is three-fold smaller.The odd ratios for autism increases when deleting or duplicating any point of pLI. This increased autism risk is similar in subgroups of individuals below or above median IQ.Once 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, behaviour, and phonological memory, whereas both equally affect motor skills.Conclusions: Autism risk conferred by duplications is less influenced by IQ compared to deletions. CNVs increase autism risk similarly in individuals with high and low IQ. Our model, trained on CNVs encompassing >4,500 genes, suggests highly polygenic properties of gene dosage with respect to autism risk. These models will help interpreting CNVs identified in the clinic.

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Section: Introductionmentioning

confidence: 74%

Section: Effect-size Of Gene Dosage On General Intelligence In Probanmentioning

confidence: 96%

Section: Unselected Cohortsmentioning

confidence: 99%

Section: Potential Applications In the Clinicmentioning

confidence: 99%

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Effects-sizes of deletions and duplications on autism risk across the genome

Douard

Zeribi

Schramm

et al. 2020

Preprint

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“…We have previously shown that linear models 19 using the sum of the "probability of being loss-of-function intolerant" (pLI) scores 20 of all genes included in a deletion can predict their effect-size on intelligence quotient (IQ) with a concordance of 75% with empirical measures.…”

Section: Introductionmentioning

confidence: 99%

Genome wide analysis of gene dosage in 24,092 individuals shows that 10,000 genes modulate cognitive ability

Huguet

Schramm

Douard

et al. 2020

Preprint

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Rare genomic Copy Number Variants (CNVs) are major contributors to neurodevelopmental disorder. The vast majority of pathogenic CNVs reported back to patients are ultra-rare and their quantitative effects on traits such as intelligence are undocumented.Here, we identified all CNVs ≥ 50 kilobase in 24,092 individuals from unselected and autism cohorts. We developed statistical models to estimate the effect-size of CNVs on intelligence based on their coding and non-coding characteristics.Measures of intolerance to haploinsufficiency best explained the effect of any deletion or duplication on general intelligence. There was no heterogeneity across unselected and autism cohorts. Validation was performed using an intraclass concordance and showed that model estimates of general intelligence were 78% accurate with mean effect-sizes previously published for 47 CNVs.Inheritance data on 27,766 CNVs showed that deletions and duplications with the same large effect-size on intelligence occur de novo at the same frequency.Our first outline for the effect sizes of all coding genes on intelligence suggests that around 10,000 genes affect this trait.

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Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

Meer¹,

Sønderby²,

Kaufmann³

et al. 2020

JAMA Psychiatry

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Writing Committee for the ENIGMA-CNV Working Group IMPORTANCE Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.OBJECTIVE To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. DESIGN, SETTING, AND PARTICIPANTSIn this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included.

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Measuring and Estimating the Effect Sizes of Copy Number Variants on General Intelligence in Community-Based Samples

Cited by 91 publications

References 46 publications

Effects-sizes of deletions and duplications on autism risk across the genome

Effects-sizes of deletions and duplications on autism risk across the genome

Genome wide analysis of gene dosage in 24,092 individuals shows that 10,000 genes modulate cognitive ability

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

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