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

Abstract

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.

Figure 1.. Venn Diagram and Flowchart for Quality Control of Arrays and Copy Number Variants (CNVs)

A, Venn diagram representing different steps of microarray selection by quality control and verification of genetic information. The blue circle represents an array without good quality control. The green circle represents individuals having discordance between pedigree information and array (sex and relationship). The red circle represents duplicated microarrays. B, Flowchart representing the steps of CNVs selection after that microarray with good quality was selected. kb indicates kilobase; seg dup, segmental duplication; and SYS, Saguenay Youth Study.

Figure 2.. Predicted Loss of Performance IQ (PIQ) for Recurrent Copy Number Variants (CNVs) and Nonrecurrent CNVs Observed in the Clinic

A, Distribution of the loss of PIQ per gene estimated by the model 4 for all RefSeq genes (N = 17 102). The black solid vertical line is the median, the dashed black vertical line is the mean, and the dashed orange vertical line is the mean individual effect of genes included in rare deletions (model 2). Of note, 36% of genes have an associated estimated loss of PIQ less than −0.67, 33% (n = 5597) are predicted to affect IQ greater than or equal to 1 point, 23% (n = 3949) by greater than or equal to 2 points, and 6% (n = 968) have maximum effect size. B, Concordance between loss of PIQ estimated by model 4 (y-axis) and loss of PIQ measured by previously published studies (x-axis) for 15 recurrent CNVs. Each point corresponds to a known recurrent CNV: (1) 17p12_(HNPP), (2) 16p12.1, (3) 15q11.2, (4) 16p13.11, (5) 1q21.1 TAR, (6) 17q12, (7) 16p11.2 Distal (SH2B1), (8) 1q21.1 Distal (Class I), (9) 15q13.3 (BP4-BP5), (10) 16p11.2 proximal (BP4-BP5), (11) 22q11.2, (12) 7q11.23 (William-Beuren), (13) 3q29 (DLG1), (14) 8p23.1, and (15) 17p11.2 (Smith-Magenis). The diagonal dashed line represents exact concordance. When loss of IQ was not directly measured in a previous study, we derived the loss of IQ from the published OR measuring the enrichment of a CNV in the neurodevelopmental clinic (open circles). Of note, the PIQ loss estimated by the model is 4.4 points for the 17q21.31 deletion, including KANSL1 a causal gene for intellectual disabilities. This is discordant with the estimated decrease of 36.3 points based on empirical data from the literature. Including this CNV, the concordance is 0.62 (95% CI, 0.20-0.85). C, Coverage of genes by the Center Hospitalier Universitaire Sainte-Justine (CHU-SJ) cohort according to significance level of CNVs. The y-axis represents the number of unique genes observed in the cohort, and the x-axis represents the number of individuals seen in the cohort. Coverage was obtained using 1000 iterations (bootstrap procedure on the order of individuals’ inclusion). D, Density of loss of PIQ estimated by the model 4 for genes included in CNVs from CHU-SJ for the different clinical significance category of CNVs. Solid lines correspond to medians, and the dashed lines correspond to means. ICC_3,1 indicates intraclass correlation coefficient (1, 3); VUS, variant of unknown significance.

Figure 3.. Association Between De Novo and IQ Loss

A, Probability of de novo estimated by model 5 (y-axis) according to the loss of performance IQ (PIQ) estimated by model 4 (x-axis) for the 897 deletions from the Center Hospitalier Universitaire Sainte-Justine cohort and 1264 deletions from the Simon simplex collection cohort for which inheritance status is available (the orange lines are all copy number variants [CNVs], and the gray lines are nonrecurrent CNVs). The de novo frequency increased even for modest associations with IQ (eg, −5 points of PIQ is associated with a de novo frequency of 7.8%). B, Concordance between de novo frequency observed in DECIPHER (x-axis) and the probability of being de novo estimated by model 5 (y-axis) for 15 recurrent CNVs. Each point corresponds to a known recurrent CNV: (1) 17p12_(HNPP), (2) 16p12.1, (3) 15q11.2, (4) 16p13.11, (5) 1q21.1 TAR, (6) 17q12, (7) 16p11.2 Distal (SH2B1), (8) 1q21.1 Distal (Class I), (9) 15q13.3 (BP4-BP5), (10) 16p11.2 proximal (BP4-BP5), (11) 22q11.2, (12) 7q11.23 (William-Beuren), (13) 3q29 (DLG1), (14) 8p23.1, and (15) 17p11.2 (Smith-Magenis). The first bisector represents the perfect concordance. ICC_3,1 indicates intraclass correlation coefficient (1, 3).