Estimating the effect-size of gene dosage on cognition across the coding genome Abbreviations: Samples: ● unselected cohorts/populations ● autism cohorts/populations ● G-Scot: generation Scotland ● IMAGEN ● CaG-Omni2.5; CaG-GSA: Cartagene (by technology) ● LBC1936: Lothian birth cohort ● SSC-Omni2.5; SSC-1Mv1; SSC-1Mv3: Simon simplex collection (by technology) ● SYS parents; SYS children: Saguenay youth study ● MSSNG ● Sainte-Justine family genetic cohort Statistics: ● n: sample size ● P: p-value ● SE: standard error ● SD: standard deviation ● ρ: correlation Genetics/genetic scores: ● pLI, ● pLI (gnomAD) ● O/E: observed over expected ● O/E-upper CI ● RVIS ● DEL score; DUP score ● PPI: protein-protein interaction ● DS ● PSD genes ● FMRP genes ● eQTL ● No. of genes Other variables: ● “type of test-cohort” variable ● g-factor: general factor ● NVIQ: non-verbal intelligence quotient ● Age in years ● z-scored measure of general intelligence 1 Supplementary Online Content Supplementary Information ........................................................................................................................... 6 1. Cohorts .............................................................................................................................................. 6 1.1. General population cohorts ...................................................................................................... 6 1.2. Disease cohorts ........................................................................................................................ 7 2. Definition of phenotypes: IQ and g-factor ........................................................................................ 8 2.1. Evaluation of IQ ....................................................................................................................... 8 2.2. G-factor computation ............................................................................................................... 9 3. Genetic information ........................................................................................................................ 11 3.1. CNV calling ........................................................................................................................... 11 3.2. CNV filtering ......................................................................................................................... 12 3.3. Genetic analysis of pairwise relatedness ................................................................................ 13 3.4. Criteria to remove outlier individual with particular CNV .................................................... 13 3.5. Definition of recurrent CNVs ................................................................................................ 13 3.6. Annotation of CNVs .............................................................................................................. 14 4. Statistical analyses .......................................................................................................................... 14 4.1. Coverage ................................................................................................................................ 14 4.2. Assessing age and sex biases in the cohorts .......................................................................... 15 4.3. Meta-analyses assessing the effect of pLI on general intelligence ........................................ 17 4.4. Mega-analysis assessing the effect of pLI or 1/LOEUF on general intelligence ................... 18 4.5. Concordance analysis between prediction of our models and literature observations ........... 21 4.6. Estimation of the probability of a de novo CNV using haploinsufficiency scores ................ 21 4.7. Estimating the effect size of genes categories by LOEUF ..................................................... 22 4.8. R packages used for statistical analyses ................................................................................. 23 Extended Data Tables .................................................................................................................................. 24 Extended Data Figures ................................................................................................................................. 47 2 List of Extended Data Tables Supplementary table 1: Correlation and concordance between NVIQ and g-factor in 3 unselected populations. .................................................................................................................................................. 24 Supplementary table 2: Estimates associated with pLI within each sample included in the meta-analyse. ...................................................................................................................................................................... 24 Supplementary table 3: Comparison of estimates associated with pLI when measuring the effect-size of CNVs on IQ and g-factor. ............................................................................................................................ 25 Supplementary table 4: Comparison of model fit for general intelligence according to annotation score. ...................................................................................................................................................................... 25 Supplementary table 5: Estimated effects of individual genic region on general intelligence according to pLI or 1/LOEUF. ......................................................................................................................................... 26 Supplementary table 6: Estimated effects of CNVs on general intelligence, for different thresholds of exonic proportion of gene overlapping a CNV that defines genes involved in sum of pLI or 1/LOEUF computation .................................................................................................................................................. 28 Supplementary table 7: Estimated effects of CNVs on general intelligence, for different thresholds of intronic proportion of gene overlapping a CNV that defines genes involved in sum of pLI or 1/LOEUF computation .................................................................................................................................................. 30 Supplementary table 8: Linear regression models including pLI x age interaction as predictor of general intelligence. .................................................................................................................................................. 31 Supplementary table 9: Linear regression models including 1/LOEUF x age interaction as predictor of general intelligence. ..................................................................................................................................... 31 Supplementary table 10: Linear regression models including pLI x sex interaction as predictor of general intelligence. .................................................................................................................................................. 32 Supplementary table 11: Linear regression models including 1/LOEUF x sex interaction as predictor of general intelligence. ..................................................................................................................................... 32 Supplementary table 12: Linear regression models performed in the mega-analysis to measure the effect of deleted or duplicated units of pLI on general intelligence on general intelligence. ................................ 33 Supplementary table 13: Linear regression models performed in the mega-analysis to measure the effect of deleted or duplicated units of 1/LOEUF on general intelligence. ........................................................... 34 Supplementary table 14 : Linear regression models performed in the mega-analysis to measure the effect of deleted or duplicated units of pLI or 1/LOEUF on general intelligence for 3 sensitivity analyses based on exclusion of individuals carrying recurrent CNV or CNV containing ID-gene. ......................................... 35 Supplementary table 15: Linear regression models performed in the mega-analysis to measure the effect of deleted or duplicated units of pLI or 1/LOEUF, by gene category (ID- and non ID-genes) on general intelligence. .................................................................................................................................................. 35 3 Supplementary table 16 : Distribution of the effect associated with deletion or duplication of genes by gene categories. ............................................................................................................................................ 36 Supplementary table 17: Estimates obtained for models performed in Ste-Justine neurodevelopmental cohort ........................................................................................................................................................... 37 Supplementary table 18: Description of the effect of 47 recurrent CNVs on general intelligence and probability of being de novo, estimated using empirical data from the literature and/or UKBB and using our models. ......................................................................................................................................................... 39 Supplementary table 19 : Detailed table of content for the de